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Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles

Abstract

A large body of evidence indicates that mitochondrial dysfunction has a major role in the pathogenesis of multiple cardiovascular disorders. Over the past 2 decades, extraordinary efforts have been focused on the development of agents that specifically target mitochondria for the treatment of cardiovascular disease. Despite such an intensive wave of investigation, no drugs specifically conceived to modulate mitochondrial functions are currently available for the clinical management of cardiovascular disease. In this Review, we discuss the therapeutic potential of targeting mitochondria in patients with cardiovascular disease, examine the obstacles that have restrained the development of mitochondria-targeting agents thus far, and identify strategies that might empower the full clinical potential of this approach.

Key points

  • Mitochondrial dysfunction is involved in the pathogenesis of multiple cardiovascular disorders, including myocardial infarction, cardiomyopathies of various aetiologies, arrhythmias, hypertension, and atherosclerosis.

  • Mitochondria are essential for the physiological activity of the cardiovascular system owing to their crucial role in bioenergetic and anabolic metabolism and their central position in intracellular Ca2+ fluxes.

  • In addition to losing their physiological functions, damaged mitochondria actively drive inflammatory responses and waves of regulated cell death that contribute to the pathogenesis of cardiovascular disease.

  • An intensive wave of investigation attempted to develop mitochondria-targeting agents for preventing or treating cardiovascular disorders in patients, with rather dismal results.

  • Molecules with improved pharmacological features, precise mechanistic insights into mitochondrial processes, and reconsidering the pathogenesis of some cardiovascular disorders are instrumental for the development of mitochondria-targeting agents with clinical use.

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Fig. 1: Contribution of mitochondrial dysfunction to cardiovascular disease.
Fig. 2: Overview of mitochondrial dynamics.
Fig. 3: Pharmacological audit trail for the development of novel mitochondria-targeting agents for clinical applications.

References

  1. Lopez-Crisosto, C. et al. Sarcoplasmic reticulum-mitochondria communication in cardiovascular pathophysiology. Nat. Rev. Cardiol. 14, 342–360 (2017).

    CAS  PubMed  Google Scholar 

  2. Mehta, M. M., Weinberg, S. E. & Chandel, N. S. Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17, 608–620 (2017).

    CAS  PubMed  Google Scholar 

  3. Galluzzi, L., Kepp, O., Trojel-Hansen, C. & Kroemer, G. Mitochondrial control of cellular life, stress, and death. Circ. Res. 111, 1198–1207 (2012).

    CAS  PubMed  Google Scholar 

  4. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018). The authors of this paper provide a comprehensive review of the pathways through which mammalian cells die in response to microenvironmental perturbations and propose a unified nomenclature for cell death on the basis of mechanistic and essential (as opposed to morphological and dispensable) aspects of the process.

    PubMed  PubMed Central  Google Scholar 

  5. Delbridge, L. M. D., Mellor, K. M., Taylor, D. J. & Gottlieb, R. A. Myocardial stress and autophagy: mechanisms and potential therapies. Nat. Rev. Cardiol. 14, 412–425 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Galluzzi, L. et al. Molecular definitions of autophagy and related processes. EMBO J. 36, 1811–1836 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Stolz, A., Ernst, A. & Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495–501 (2014).

    CAS  PubMed  Google Scholar 

  9. Sica, V. et al. Organelle-specific initiation of autophagy. Mol. Cell 59, 522–539 (2015).

    CAS  PubMed  Google Scholar 

  10. Harper, J. W., Ordureau, A. & Heo, J. M. Building and decoding ubiquitin chains for mitophagy. Nat. Rev. Mol. Cell Biol. 19, 93–108 (2018).

    CAS  PubMed  Google Scholar 

  11. Murphy, E. et al. Mitochondrial function, biology, and role in disease: a scientific statement from the American Heart Association. Circ. Res. 118, 1960–1991 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schulze, P. C., Drosatos, K. & Goldberg, I. J. Lipid use and misuse by the heart. Circ. Res. 118, 1736–1751 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu, Y. F., Chen, Y. J., Lin, Y. J. & Chen, S. A. Inflammation and the pathogenesis of atrial fibrillation. Nat. Rev. Cardiol. 12, 230–243 (2015).

    CAS  PubMed  Google Scholar 

  14. Gistera, A. & Hansson, G. K. The immunology of atherosclerosis. Nat. Rev. Nephrol. 13, 368–380 (2017).

    PubMed  Google Scholar 

  15. Amgalan, D., Chen, Y. & Kitsis, R. N. Death receptor signaling in the heart: cell survival, apoptosis, and necroptosis. Circulation 136, 743–746 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. Suomalainen, A. & Battersby, B. J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. 19, 77–92 (2018).

    CAS  PubMed  Google Scholar 

  17. Bravo-San Pedro, J. M., Kroemer, G. & Galluzzi, L. Autophagy and mitophagy in cardiovascular disease. Circ. Res. 120, 1812–1824 (2017).

    CAS  PubMed  Google Scholar 

  18. Brown, D. A. et al. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat. Rev. Cardiol. 14, 238–250 (2017).

    CAS  PubMed  Google Scholar 

  19. Andreux, P. A., Houtkooper, R. H. & Auwerx, J. Pharmacological approaches to restore mitochondrial function. Nat. Rev. Drug Discov. 12, 465–483 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hill, B. G. & Schulze, P. C. Insights into metabolic remodeling of the hypertrophic and failing myocardium. Circ. Heart Fail. 7, 874–876 (2014).

    PubMed  PubMed Central  Google Scholar 

  21. Krishnan, J. et al. Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 9, 512–524 (2009).

    CAS  PubMed  Google Scholar 

  22. Sun, H. et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133, 2038–2049 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sansbury, B. E. et al. Metabolomic analysis of pressure-overloaded and infarcted mouse hearts. Circ. Heart Fail. 7, 634–642 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Choi, Y. S. et al. Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion. J. Mol. Cell. Cardiol. 100, 64–71 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014). This study provides an elegant demonstration that succinate accumulating in the ischaemic myocardium drives an intense oxidative burst at respiratory complex I during reperfusion, thereby contributing to the pathogenesis of ischaemia–reperfusion injury.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Dodd, M. S. et al. Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. Circ. Cardiovasc. Imaging 7, 895–904 (2014).

    PubMed  PubMed Central  Google Scholar 

  27. Wu, S. P. et al. Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nat. Commun. 6, 8245 (2015).

    PubMed  Google Scholar 

  28. Moll, S. & Varga, E. A. Homocysteine and MTHFR mutations. Circulation 132, e6–e9 (2015).

    CAS  PubMed  Google Scholar 

  29. Rodenburg, R. J. Mitochondrial complex I-linked disease. Biochim. Biophys. Acta 1857, 938–945 (2016).

    CAS  PubMed  Google Scholar 

  30. Joza, N. et al. Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol. Cell. Biol. 25, 10261–10272 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, H. et al. Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy. Proc. Natl Acad. Sci. USA 97, 3467–3472 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Iliceto, S. et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial. J. Am. Coll. Cardiol. 26, 380–387 (1995).

    CAS  PubMed  Google Scholar 

  33. Davini, P., Bigalli, A., Lamanna, F. & Boem, A. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp. Clin. Res. 18, 355–365 (1992).

    CAS  PubMed  Google Scholar 

  34. Iyer, R., Gupta, A., Khan, A., Hiremath, S. & Lokhandwala, Y. Does left ventricular function improve with L-carnitine after acute myocardial infarction? J. Postgrad. Med. 45, 38–41 (1999).

    CAS  PubMed  Google Scholar 

  35. Tarantini, G. et al. Metabolic treatment with L-carnitine in acute anterior ST segment elevation myocardial infarction. A randomized controlled trial. Cardiology 106, 215–223 (2006).

    CAS  PubMed  Google Scholar 

  36. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Schmidt-Schweda, S. & Holubarsch, C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin. Sci. (Lond.) 99, 27–35 (2000).

    CAS  Google Scholar 

  38. Holubarsch, C. J. et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci. (Lond.) 113, 205–212 (2007).

    CAS  Google Scholar 

  39. Chong, C. R., Ong, G. J. & Horowitz, J. D. Emerging drugs for the treatment of angina pectoris. Expert Opin. Emerg. Drugs 21, 365–376 (2016).

    CAS  PubMed  Google Scholar 

  40. Beadle, R. M. et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail. 3, 202–211 (2015).

    PubMed  Google Scholar 

  41. Yin, X. et al. Effects of perhexiline-induced fuel switch on the cardiac proteome and metabolome. J. Mol. Cell. Cardiol. 55, 27–30 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Marino, G. et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725 (2014).

    CAS  PubMed  Google Scholar 

  43. Abozguia, K. et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 122, 1562–1569 (2010).

    CAS  PubMed  Google Scholar 

  44. Senanayake, E. L. et al. Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery. Eur. J. Cardiothorac. Surg. 48, 354–362 (2015).

    PubMed  Google Scholar 

  45. Drury, N. E. et al. The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial. Eur. J. Cardiothorac. Surg. 47, 464–472 (2015).

    PubMed  Google Scholar 

  46. Zhang, N. et al. The effectiveness of preoperative trimetazidine on myocardial preservation in coronary artery bypass graft patients: a systematic review and meta-analysis. Cardiology 131, 86–96 (2015).

    CAS  PubMed  Google Scholar 

  47. Tuunanen, H. et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation 118, 1250–1258 (2008).

    CAS  PubMed  Google Scholar 

  48. Vitale, C. et al. Trimetazidine improves exercise performance in patients with peripheral arterial disease. Pharmacol. Res. 63, 278–283 (2011).

    CAS  PubMed  Google Scholar 

  49. Rosano, G. M., Vitale, C., Sposato, B., Mercuro, G. & Fini, M. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc. Diabetol. 2, 16 (2003).

    PubMed  PubMed Central  Google Scholar 

  50. Marin, T. L. et al. AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Sci. Signal. 10, eaaf7478 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. Leung, J. M. et al. An initial multicenter, randomized controlled trial on the safety and efficacy of acadesine in patients undergoing coronary artery bypass graft surgery. SPI Research Group. Anesth. Analg. 78, 420–434 (1994).

    CAS  PubMed  Google Scholar 

  52. Menasche, P., Jamieson, W. R., Flameng, W. & Davies, M. K. Acadesine: a new drug that may improve myocardial protection in coronary artery bypass grafting. Results of the first international multicenter study. Multinational Acadesine Study Group. J. Thorac. Cardiovasc. Surg. 110, 1096–1106 (1995).

    CAS  PubMed  Google Scholar 

  53. Newman, M. F. et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA 308, 157–164 (2012).

    CAS  PubMed  Google Scholar 

  54. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).

    CAS  PubMed  Google Scholar 

  56. Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423, 181–185 (2003). References 55 and 56 are among the first studies to demonstrate that sirtuin activation by calorie restriction or specific pharmacological agents extends the lifespan of Saccharomyces cerevisiae.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Bonkowski, M. S. & Sinclair, D. A. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17, 679–690 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hershberger, K. A., Martin, A. S. & Hirschey, M. D. Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases. Nat. Rev. Nephrol. 13, 213–225 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Cheng, H. L. et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl Acad. Sci. USA 100, 10794–10799 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Nadtochiy, S. M. et al. SIRT1-mediated acute cardioprotection. Am. J. Physiol. Heart Circ. Physiol. 301, H1506–H1512 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).

    CAS  PubMed  Google Scholar 

  62. Alcendor, R. R. et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 100, 1512–1521 (2007).

    CAS  PubMed  Google Scholar 

  63. Sundaresan, N. R. et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758–2771 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Hafner, A. V. et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2, 914–923 (2010).

    CAS  Google Scholar 

  65. Tang, X. et al. SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation 136, 2051–2067 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Sadhukhan, S. et al. Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc. Natl Acad. Sci. USA 113, 4320–4325 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sundaresan, N. R. et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat. Med. 18, 1643–1650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Vakhrusheva, O. et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102, 703–710 (2008).

    CAS  PubMed  Google Scholar 

  69. Luo, Y. X. et al. SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity. Eur. Heart J. 38, 1389–1398 (2017).

    CAS  PubMed  Google Scholar 

  70. Hariharan, N. et al. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ. Res. 107, 1470–1482 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Yang, W. et al. Mitochondrial sirtuin network reveals dynamic SIRT3-dependent deacetylation in response to membrane depolarization. Cell 167, 985–1000.e21 (2016). This article elucidates the interactome of mitochondrial sirtuins and identifies a physical interaction between SIRT3 and the F 1 F o ATP synthase that supports physiological metabolism in healthy cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004).

    CAS  PubMed  Google Scholar 

  73. Baur, J. A. & Sinclair, D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Discov. 5, 493–506 (2006).

    CAS  PubMed  Google Scholar 

  74. Pillai, V. B. et al. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat. Commun. 6, 6656 (2015).

    CAS  PubMed  Google Scholar 

  75. Chen, Y. X., Zhang, M., Cai, Y., Zhao, Q. & Dai, W. The Sirt1 activator SRT1720 attenuates angiotensin II-induced atherosclerosis in apoE(-)/(-) mice through inhibiting vascular inflammatory response. Biochem. Biophys. Res. Commun. 465, 732–738 (2015).

    CAS  PubMed  Google Scholar 

  76. Chan, A. Y. et al. Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt. J. Biol. Chem. 283, 24194–24201 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Sulaiman, M. et al. Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 298, H833–H843 (2010).

    CAS  PubMed  Google Scholar 

  78. Martin, A. S. et al. Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI Insight 2, 93885 (2017).

    PubMed  Google Scholar 

  79. Zhang, R. et al. Short-term administration of nicotinamide mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. J. Mol. Cell. Cardiol. 112, 64–73 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yamamoto, T. et al. Nicotinamide mononucleotide, an intermediate of NAD + synthesis, protects the heart from ischemia and reperfusion. PLoS ONE 9, e98972 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Bo, S. et al. Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial. Pharmacol. Res. 111, 896–905 (2016).

    CAS  PubMed  Google Scholar 

  82. Marques, B. et al. Beneficial effects of acute trans-resveratrol supplementation in treated hypertensive patients with endothelial dysfunction. Clin. Exp. Hypertens. 40, 218–223 (2018).

    CAS  PubMed  Google Scholar 

  83. Magyar, K. et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 50, 179–187 (2012).

    CAS  PubMed  Google Scholar 

  84. Krueger, J. G. et al. A randomized, placebo-controlled study of SRT2104, a SIRT1 activator, in patients with moderate to severe psoriasis. PLoS ONE 10, e0142081 (2015).

    PubMed  PubMed Central  Google Scholar 

  85. Mishra, P. & Chan, D. C. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat. Rev. Mol. Cell Biol. 15, 634–646 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Burte, F., Carelli, V., Chinnery, P. F. & Yu-Wai-Man, P. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat. Rev. Neurol. 11, 11–24 (2015).

    CAS  PubMed  Google Scholar 

  87. Piquereau, J. et al. Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload. Cardiovasc. Res. 94, 408–417 (2012).

    CAS  PubMed  Google Scholar 

  88. Wai, T. et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350, aad0116 (2015). The authors of this paper elegantly demonstrate that genetic interventions enabling accelerated OPA1 proteolysis profoundly alter mitochondrial metabolism to cause dilated cardiomyopathy and HF.

    PubMed  Google Scholar 

  89. Samant, S. A. et al. SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol. Cell. Biol. 34, 807–819 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. Chen, Y., Liu, Y. & Dorn, G. W. II. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ. Res. 109, 1327–1331 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Song, M., Franco, A., Fleischer, J. A., Zhang, L. & Dorn, G. W. II. Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab. 26, 872–883.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Hall, A. R. et al. Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. Cell Death Dis. 7, e2238 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cahill, T. J. et al. Resistance of dynamin-related protein 1 oligomers to disassembly impairs mitophagy, resulting in myocardial inflammation and heart failure. J. Biol. Chem. 290, 25907–25919 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Papanicolaou, K. N. et al. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol. Cell. Biol. 31, 1309–1328 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen, Y. & Dorn, G. W. II. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471–475 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yu, H. et al. Mitofusin 2 inhibits angiotensin II-induced myocardial hypertrophy. J. Cardiovasc. Pharmacol. Ther. 16, 205–211 (2011).

    CAS  PubMed  Google Scholar 

  97. Gong, G. et al. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350, aad2459 (2015). This article reports that cardiac deletion of Park2 or overexpression of MFN2-AA from birth (but not after weaning) blocks postnatal mitophagy-dependent mitochondrial maturation, which is essential for survival.

    PubMed  PubMed Central  Google Scholar 

  98. Coronado, M. et al. Physiological mitochondrial fragmentation is a normal cardiac adaptation to increased energy demand. Circ. Res. 122, 282–295 (2018).

    CAS  PubMed  Google Scholar 

  99. Shirakabe, A. et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation 133, 1249–1263 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ikeda, Y. et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ. Res. 116, 264–278 (2015).

    CAS  PubMed  Google Scholar 

  101. Fang, L. et al. Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. Life Sci. 80, 2154–2160 (2007).

    CAS  PubMed  Google Scholar 

  102. Javadov, S. et al. Expression of mitochondrial fusion-fission proteins during post-infarction remodeling: the effect of NHE-1 inhibition. Basic Res. Cardiol. 106, 99–109 (2011).

    CAS  PubMed  Google Scholar 

  103. Chen, L., Gong, Q., Stice, J. P. & Knowlton, A. A. Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc. Res. 84, 91–99 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Guo, X. et al. Mitofusin 2 triggers vascular smooth muscle cell apoptosis via mitochondrial death pathway. Circ. Res. 101, 1113–1122 (2007).

    CAS  PubMed  Google Scholar 

  105. Chen, K. H. et al. Dysregulation of HSG triggers vascular proliferative disorders. Nat. Cell Biol. 6, 872–883 (2004).

    CAS  PubMed  Google Scholar 

  106. Sharp, W. W. et al. Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. FASEB J. 28, 316–326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ong, S. B. et al. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121, 2012–2022 (2010).

    CAS  PubMed  Google Scholar 

  108. Ishikita, A. et al. Nanoparticle-mediated delivery of mitochondrial division inhibitor 1 to the myocardium protects the heart from ischemia-reperfusion injury through inhibition of mitochondria outer membrane permeabilization: a new therapeutic modality for acute myocardial infarction. J. Am. Heart Assoc. 5, e003872 (2016).

    PubMed  PubMed Central  Google Scholar 

  109. Givvimani, S. et al. Mitochondrial division/mitophagy inhibitor (Mdivi) ameliorates pressure overload induced heart failure. PLoS ONE 7, e32388 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Gharanei, M., Hussain, A., Janneh, O. & Maddock, H. Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: a mitochondrial division/mitophagy inhibitor. PLoS ONE 8, e77713 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Bordt, E. A. et al. The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species. Dev. Cell 40, 583–594.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Tian, L. et al. Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. J. Mol. Med. (Berl.) 95, 381–393 (2017).

    CAS  Google Scholar 

  113. Disatnik, M. H. et al. Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long-term cardiac dysfunction. J. Am. Heart Assoc. 2, e000461 (2013).

    PubMed  PubMed Central  Google Scholar 

  114. Gao, D. et al. Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart. PLoS ONE 8, e60967 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Franco, A. et al. Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature 540, 74–79 (2016). The authors generate a cell-permeant small peptide that can restore the ability of mutant MFN2 to mediate mitochondrial fusion.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Billia, F. et al. PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc. Natl Acad. Sci. USA 108, 9572–9577 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Song, M. et al. Interdependence of parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts. Circ. Res. 117, 346–351 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bhandari, P., Song, M., Chen, Y., Burelle, Y. & Dorn, G. W. II. Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin. Circ. Res. 114, 257–265 (2014).

    CAS  PubMed  Google Scholar 

  119. Dorn, G. W. II. Mitochondrial pruning by Nix and BNip3: an essential function for cardiac-expressed death factors. J. Cardiovasc. Transl Res. 3, 374–383 (2010).

    PubMed  PubMed Central  Google Scholar 

  120. Nakai, A. et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat. Med. 13, 619–624 (2007).

    CAS  PubMed  Google Scholar 

  121. Taneike, M. et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6, 600–606 (2010).

    CAS  PubMed  Google Scholar 

  122. Zaglia, T. et al. Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy. J. Clin. Invest. 124, 2410–2424 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Nishino, I. et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910 (2000).

    CAS  PubMed  Google Scholar 

  124. Xu, W. et al. Lethal cardiomyopathy in mice lacking transferrin receptor in the heart. Cell Rep. 13, 533–545 (2015).

    PubMed  PubMed Central  Google Scholar 

  125. Hoshino, A. et al. Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat. Commun. 4, 2308 (2013).

    PubMed  Google Scholar 

  126. Zhao, W. et al. Atg5 deficiency-mediated mitophagy aggravates cardiac inflammation and injury in response to angiotensin II. Free Radic. Biol. Med. 69, 108–115 (2014).

    CAS  PubMed  Google Scholar 

  127. Liao, X. et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545–553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Razani, B. et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 15, 534–544 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Sciarretta, S. et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 125, 1134–1146 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487–511 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Oka, T. et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485, 251–255 (2012). This study is the first demonstration that defects in the autophagic degradation of mtDNA result in the activation of a TLR9-dependent inflammatory response that contributes to the pathogenesis of dilated cardiomyopathy.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang, Z. et al. Mitochondrial DNA-LL-37 complex promotes atherosclerosis by escaping from autophagic recognition. Immunity 43, 1137–1147 (2015).

    CAS  PubMed  Google Scholar 

  133. Bhuiyan, M. S. et al. Enhanced autophagy ameliorates cardiac proteinopathy. J. Clin. Invest. 123, 5284–5297 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Hoshino, A. et al. p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia. J. Mol. Cell. Cardiol. 52, 175–184 (2012).

    CAS  PubMed  Google Scholar 

  135. Maejima, Y. et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat. Med. 19, 1478–1488 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu, X. et al. Ablation of ALCAT1 mitigates hypertrophic cardiomyopathy through effects on oxidative stress and mitophagy. Mol. Cell. Biol. 32, 4493–4504 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Zummo, F. P. et al. Glucagon-like peptide 1 protects pancreatic beta-cells from death by increasing autophagic flux and restoring lysosomal function. Diabetes 66, 1272–1285 (2017).

    CAS  PubMed  Google Scholar 

  138. Krech, J. et al. Moderate therapeutic hypothermia induces multimodal protective effects in oxygen-glucose deprivation/reperfusion injured cardiomyocytes. Mitochondrion 35, 1–10 (2017).

    CAS  PubMed  Google Scholar 

  139. Lu, W. et al. Mitochondrial protein PGAM5 regulates mitophagic protection against cell necroptosis. PLoS ONE 11, e0147792 (2016).

    PubMed  PubMed Central  Google Scholar 

  140. Marchi, S. et al. Defective autophagy is a key feature of cerebral cavernous malformations. EMBO Mol. Med. 7, 1403–1417 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Tannous, P. et al. Autophagy is an adaptive response in desmin-related cardiomyopathy. Proc. Natl Acad. Sci. USA 105, 9745–9750 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhu, H. et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J. Clin. Invest. 117, 1782–1793 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Matsui, Y. et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 100, 914–922 (2007).

    CAS  PubMed  Google Scholar 

  144. Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Elgendy, M. et al. Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner. Nat. Commun. 5, 5637 (2014).

    CAS  PubMed  Google Scholar 

  146. Huang, C. et al. Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS ONE 6, e20975 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Zesiewicz, T. A. et al. Heart failure in Parkinson’s disease: analysis of the United States medicare current beneficiary survey. Parkinsonism Relat. Disord. 10, 417–420 (2004).

    CAS  PubMed  Google Scholar 

  148. Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016). This study demonstrates that oral supplementation of the natural polyamine spermidine extends the lifespan of mice as it exerts cardioprotective effects in the ageing myocardium that depend on the core autophagy protein ATG5.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Pietrocola, F. et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516 (2015).

    CAS  PubMed  Google Scholar 

  150. Eisenberg, T. et al. Dietary spermidine for lowering high blood pressure. Autophagy 13, 767–769 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Dai, D. F. et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13, 529–539 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Yan, L. et al. Calorie restriction can reverse, as well as prevent, aging cardiomyopathy. Age (Dordr.) 35, 2177–2182 (2013).

    Google Scholar 

  153. Wu, X. et al. Impaired autophagy contributes to adverse cardiac remodeling in acute myocardial infarction. PLoS ONE 9, e112891 (2014).

    PubMed  PubMed Central  Google Scholar 

  154. Goh, S. S. et al. The red wine antioxidant resveratrol prevents cardiomyocyte injury following ischemia-reperfusion via multiple sites and mechanisms. Antioxid. Redox Signal. 9, 101–113 (2007).

    CAS  PubMed  Google Scholar 

  155. Kanamori, H. et al. Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion. Am. J. Physiol. Heart Circ. Physiol. 300, H2261–H2271 (2011).

    CAS  PubMed  Google Scholar 

  156. Liu, B. et al. Puerarin prevents cardiac hypertrophy induced by pressure overload through activation of autophagy. Biochem. Biophys. Res. Commun. 464, 908–915 (2015).

    CAS  PubMed  Google Scholar 

  157. Garg, S., Bourantas, C. & Serruys, P. W. New concepts in the design of drug-eluting coronary stents. Nat. Rev. Cardiol. 10, 248–260 (2013).

    CAS  PubMed  Google Scholar 

  158. Marx, S. O. & Marks, A. R. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 104, 852–855 (2001).

    CAS  PubMed  Google Scholar 

  159. Zhang, Y. et al. Rapamycin promotes the autophagic degradation of oxidized low-density lipoprotein in human umbilical vein endothelial cells. J. Vasc. Res. 52, 210–219 (2015).

    CAS  PubMed  Google Scholar 

  160. Martinet, W., Verheye, S. & De Meyer, G. R. Everolimus-induced mTOR inhibition selectively depletes macrophages in atherosclerotic plaques by autophagy. Autophagy 3, 241–244 (2007).

    CAS  PubMed  Google Scholar 

  161. Verheye, S. et al. Selective clearance of macrophages in atherosclerotic plaques by autophagy. J. Am. Coll. Cardiol. 49, 706–715 (2007).

    CAS  PubMed  Google Scholar 

  162. Pietrocola, F. et al. Aspirin recapitulates features of caloric restriction. Cell Rep. 22, 2395–2407 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Andres, A. M. et al. Mitophagy is required for acute cardioprotection by simvastatin. Antioxid. Redox Signal. 21, 1960–1973 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. McLendon, P. M. et al. Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy. Proc. Natl Acad. Sci. USA 111, E5178–E5186 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Xie, M. et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 129, 1139–1151 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Kho, C., Lee, A. & Hajjar, R. J. Altered sarcoplasmic reticulum calcium cycling—targets for heart failure therapy. Nat. Rev. Cardiol. 9, 717–733 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011). References 167 and 168 are the first studies to identify and characterize the long-sought protein responsible for ruthenium red-sensitive mitochondrial Ca 2+ import, which was named MCU.

    PubMed  PubMed Central  Google Scholar 

  169. Boyman, L., Williams, G. S., Khananshvili, D., Sekler, I. & Lederer, W. J. NCLX: the mitochondrial sodium calcium exchanger. J. Mol. Cell. Cardiol. 59, 205–213 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Williams, G. S., Boyman, L. & Lederer, W. J. Mitochondrial calcium and the regulation of metabolism in the heart. J. Mol. Cell. Cardiol. 78, 35–45 (2015).

    CAS  PubMed  Google Scholar 

  171. Bonora, M. et al. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 34, 1475–1486 (2015).

    CAS  PubMed  Google Scholar 

  172. Santulli, G., Xie, W., Reiken, S. R. & Marks, A. R. Mitochondrial calcium overload is a key determinant in heart failure. Proc. Natl Acad. Sci. USA 112, 11389–11394 (2015). The authors provide robust evidence in support of the notion that diastolic Ca 2+ leaks from the sarcoplasmic reticulum lead to mitochondrial Ca 2+ overload, which contributes to the pathogenesis of HF.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Pan, X. et al. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat. Cell Biol. 15, 1464–1472 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Luongo, T. S. et al. The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. Cell Rep. 12, 23–34 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Kwong, J. Q. et al. The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Rep. 12, 15–22 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Rasmussen, T. P. et al. Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc. Natl Acad. Sci. USA 112, 9129–9134 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Luongo, T. S. et al. The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature 545, 93–97 (2017). This article demonstrates that deletion of Slc8b1 from the adult heart causes sudden death as a consequence of severe myocardial dysfunction and fulminant HF.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Venetucci, L., Denegri, M., Napolitano, C. & Priori, S. G. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat. Rev. Cardiol. 9, 561–575 (2012).

    CAS  PubMed  Google Scholar 

  179. Joiner, M. L. et al. CaMKII determines mitochondrial stress responses in heart. Nature 491, 269–273 (2012). The authors identify a functional link between CaMKII and MPT-driven regulated necrosis, namely, MCU-dependent Ca 2+ overload, which contributes to ischaemia–reperfusion injury in the mouse myocardium.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Xu, S. et al. CaMKII induces permeability transition through Drp1 phosphorylation during chronic beta-AR stimulation. Nat. Commun. 7, 13189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Fazal, L. et al. Multifunctional mitochondrial Epac1 controls myocardial cell death. Circ. Res. 120, 645–657 (2017).

    CAS  PubMed  Google Scholar 

  182. Westenbrink, B. D. et al. Mitochondrial reprogramming induced by CaMKIIdelta mediates hypertrophy decompensation. Circ. Res. 116, e28–e39 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Maione, A. S. et al. Cellular subtype expression and activation of CaMKII regulate the fate of atherosclerotic plaque. Atherosclerosis 256, 53–61 (2017).

    CAS  PubMed  Google Scholar 

  184. Macle, L. & Nattel, S. Arrhythmias in 2015: advances in drug, ablation, and device therapy for cardiac arrhythmias. Nat. Rev. Cardiol. 13, 67–68 (2016).

    CAS  PubMed  Google Scholar 

  185. Liu, T. et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ. Res. 115, 44–54 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Tanaka, H. et al. Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. Br. J. Pharmacol. 135, 1096–1100 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Kon, N. et al. DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter. Cell Death Discov. 3, 17045 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Arduino, D. M. et al. Systematic identification of MCU modulators by orthogonal interspecies chemical screening. Mol. Cell 67, 711–723.e7 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Thu, V. T. et al. NecroX-5 prevents hypoxia/reoxygenation injury by inhibiting the mitochondrial calcium uniporter. Cardiovasc. Res. 94, 342–350 (2012).

    CAS  PubMed  Google Scholar 

  190. Pellicena, P. & Schulman, H. CaMKII inhibitors: from research tools to therapeutic agents. Front. Pharmacol. 5, 21 (2014).

    PubMed  PubMed Central  Google Scholar 

  191. Shadel, G. S. & Horvath, T. L. Mitochondrial ROS signaling in organismal homeostasis. Cell 163, 560–569 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Galluzzi, L., Kepp, O., Krautwald, S., Kroemer, G. & Linkermann, A. Molecular mechanisms of regulated necrosis. Semin. Cell Dev. Biol. 35, 24–32 (2014).

    CAS  PubMed  Google Scholar 

  193. Sam, F. et al. Increased reactive oxygen species production and functional alterations in antioxidant enzymes in human failing myocardium. J. Card. Fail. 11, 473–480 (2005).

    CAS  PubMed  Google Scholar 

  194. Montaigne, D. et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 130, 554–564 (2014).

    CAS  PubMed  Google Scholar 

  195. Dai, D. F. et al. Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J. Am. Coll. Cardiol. 58, 73–82 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Mallat, Z. et al. Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 97, 1536–1539 (1998).

    CAS  PubMed  Google Scholar 

  197. Kono, Y. et al. Elevated levels of oxidative DNA damage in serum and myocardium of patients with heart failure. Circ. J. 70, 1001–1005 (2006).

    CAS  PubMed  Google Scholar 

  198. Canton, M. et al. Oxidation of myofibrillar proteins in human heart failure. J. Am. Coll. Cardiol. 57, 300–309 (2011).

    CAS  PubMed  Google Scholar 

  199. Ide, T. et al. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ. Res. 85, 357–363 (1999).

    CAS  PubMed  Google Scholar 

  200. Judge, S., Jang, Y. M., Smith, A., Hagen, T. & Leeuwenburgh, C. Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J. 19, 419–421 (2005).

    CAS  PubMed  Google Scholar 

  201. Ungvari, Z. et al. Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am. J. Physiol. Heart Circ. Physiol. 293, H37–H47 (2007).

    CAS  PubMed  Google Scholar 

  202. Vendrov, A. E. et al. Attenuated superoxide dismutase 2 activity induces atherosclerotic plaque instability during aging in hyperlipidemic mice. J. Am. Heart Assoc. 6, e006775 (2017).

    PubMed  PubMed Central  Google Scholar 

  203. Nakada, Y. et al. Hypoxia induces heart regeneration in adult mice. Nature 541, 222–227 (2017). This study is the first report demonstrating that gradual respiratory hypoxia, resulting in severe systemic hypoxaemia, after MI induces a robust regenerative response that ameliorates disease outcome, at least in mice.

    CAS  PubMed  Google Scholar 

  204. Conrad, M. et al. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol. Cell. Biol. 24, 9414–9423 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Kiermayer, C. et al. Heart-specific knockout of the mitochondrial thioredoxin reductase (Txnrd2) induces metabolic and contractile dysfunction in the aging myocardium. J. Am. Heart Assoc. 4, e002153 (2015).

    PubMed  PubMed Central  Google Scholar 

  206. Mortensen, S. A. et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2, 641–649 (2014).

    PubMed  Google Scholar 

  207. Oleck, S. & Ventura, H. O. Coenzyme Q10 and utility in heart failure: just another supplement? Curr. Heart Fail. Rep. 13, 190–195 (2016).

    CAS  PubMed  Google Scholar 

  208. Judy, W. V., Stogsdill, W. W. & Folkers, K. Myocardial preservation by therapy with coenzyme Q10 during heart surgery. Clin. Investig. 71, S155–S161 (1993).

    CAS  PubMed  Google Scholar 

  209. Singh, R. B. et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc. Drugs Ther. 12, 347–353 (1998).

    CAS  PubMed  Google Scholar 

  210. Brown, B. G. et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N. Engl. J. Med. 345, 1583–1592 (2001).

    CAS  PubMed  Google Scholar 

  211. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 23–33 (2002). This large, randomized, placebo-controlled clinical trial demonstrates that antioxidant vitamin supplementation does not produce any significant reduction in 5-year mortality from, or incidence of, any type of CVD.

    Google Scholar 

  212. Stephens, N. G. et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 347, 781–786 (1996).

    CAS  PubMed  Google Scholar 

  213. Sesso, H. D. et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA 300, 2123–2133 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Lee, I. M. et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 294, 56–65 (2005).

    CAS  PubMed  Google Scholar 

  215. Magliano, D. et al. The Melbourne Atherosclerosis Vitamin E Trial (MAVET): a study of high dose vitamin E in smokers. Eur. J. Cardiovasc. Prev. Rehabil. 13, 341–347 (2006).

    PubMed  Google Scholar 

  216. Singh, R. B. et al. Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction. Mol. Cell. Biochem. 246, 75–82 (2003).

    CAS  PubMed  Google Scholar 

  217. Cho, J. et al. Potent mitochondria-targeted peptides reduce myocardial infarction in rats. Coron. Artery Dis. 18, 215–220 (2007).

    PubMed  Google Scholar 

  218. Eirin, A. et al. Restoration of mitochondrial cardiolipin attenuates cardiac damage in swine renovascular hypertension. J. Am. Heart Assoc. 5, e003118 (2016).

    PubMed  PubMed Central  Google Scholar 

  219. Lu, H. I. et al. Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice. Acta Pharmacol. Sin. 37, 589–603 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Kroller-Schon, S. et al. Peroxisome proliferator-activated receptor gamma, coactivator 1alpha deletion induces angiotensin II-associated vascular dysfunction by increasing mitochondrial oxidative stress and vascular inflammation. Arterioscler. Thromb. Vasc. Biol. 33, 1928–1935 (2013).

    PubMed  Google Scholar 

  221. Ribeiro Junior, R. F. et al. MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload. Free Radic. Biol. Med. 117, 18–29 (2018).

    PubMed  PubMed Central  Google Scholar 

  222. Adlam, V. J. et al. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 19, 1088–1095 (2005).

    CAS  PubMed  Google Scholar 

  223. Sloan, R. C. et al. Mitochondrial permeability transition in the diabetic heart: contributions of thiol redox state and mitochondrial calcium to augmented reperfusion injury. J. Mol. Cell. Cardiol. 52, 1009–1018 (2012).

    CAS  PubMed  Google Scholar 

  224. Brown, D. A. et al. Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia. J. Cardiovasc. Pharmacol. Ther. 19, 121–132 (2014).

    CAS  PubMed  Google Scholar 

  225. Shi, J. et al. Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart. Life Sci. 141, 170–178 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Zhang, M. et al. Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet. PLoS ONE 12, e0185688 (2017).

    PubMed  PubMed Central  Google Scholar 

  227. Saad, A. et al. Phase 2a clinical trial of mitochondrial protection (elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis. Circ. Cardiovasc. Interv. 10, e005487 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Gibson, C. M. et al. EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. Eur. Heart J. 37, 1296–1303 (2016).

    CAS  PubMed  Google Scholar 

  229. Daubert, M. A. et al. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide. Circ. Heart Fail. 10, e004389 (2017).

    CAS  PubMed  Google Scholar 

  230. Ruparelia, N., Chai, J. T., Fisher, E. A. & Choudhury, R. P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017).

    CAS  PubMed  Google Scholar 

  231. Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Mills, E. L., Kelly, B. & O’Neill, L. A. J. Mitochondria are the powerhouses of immunity. Nat. Immunol. 18, 488–498 (2017).

    CAS  PubMed  Google Scholar 

  233. Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondria: master regulators of danger signalling. Nat. Rev. Mol. Cell Biol. 13, 780–788 (2012).

    CAS  PubMed  Google Scholar 

  234. Durga Devi, T. et al. Aggravated postinfarct heart failure in type 2 diabetes is associated with impaired mitophagy and exaggerated inflammasome activation. Am. J. Pathol. 187, 2659–2673 (2017).

    CAS  PubMed  Google Scholar 

  235. Mao, Y. et al. STING-IRF3 triggers endothelial inflammation in response to free fatty acid-induced mitochondrial damage in diet-induced obesity. Arterioscler. Thromb. Vasc. Biol. 37, 920–929 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Kepp, O., Loos, F., Liu, P. & Kroemer, G. Extracellular nucleosides and nucleotides as immunomodulators. Immunol. Rev. 280, 83–92 (2017).

    CAS  PubMed  Google Scholar 

  238. Dieude, M. et al. Cardiolipin binds to CD1d and stimulates CD1d-restricted gammadelta T cells in the normal murine repertoire. J. Immunol. 186, 4771–4781 (2011).

    CAS  PubMed  Google Scholar 

  239. Galluzzi, L., Vanpouille-Box, C., Bakhoum, S. F. & Demaria, S. Snapshot: CGAS-STING signaling. Cell 173, 276–276.e1 (2018).

    CAS  PubMed  Google Scholar 

  240. Cao, D. et al. Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury. Circulation 137, 2613–2634 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).

    CAS  PubMed  Google Scholar 

  242. King, K. R. et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat. Med. 23, 1481–1487 (2017). This study is an elegant demonstration that interferon regulatory factor 3 (IRF3)-dependent type I interferon synthesis leads to the establishment of an inflammatory response that aggravates disease outcome after MI.

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Sandanger, O. et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc. Res. 99, 164–174 (2013).

    CAS  PubMed  Google Scholar 

  244. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Chamberlain, J. et al. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding. PLoS ONE 4, e5073 (2009).

    PubMed  PubMed Central  Google Scholar 

  246. Merhi-Soussi, F. et al. Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice. Cardiovasc. Res. 66, 583–593 (2005).

    CAS  PubMed  Google Scholar 

  247. Gidlof, O. et al. A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events. PLoS ONE 7, e37491 (2012).

    PubMed  PubMed Central  Google Scholar 

  248. Marchetti, C. et al. A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse. J. Cardiovasc. Pharmacol. 63, 316–322 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Marchetti, C. et al. Pharmacologic inhibition of the NLRP3 inflammasome preserves cardiac function after ischemic and nonischemic injury in the mouse. J. Cardiovasc. Pharmacol. 66, 1–8 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Granado, M. et al. Altered expression of P2Y2 and P2X7 purinergic receptors in the isolated rat heart mediates ischemia-reperfusion injury. Vascul. Pharmacol. 73, 96–103 (2015).

    CAS  PubMed  Google Scholar 

  251. McCarthy, C. G. et al. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc. Res. 107, 119–130 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Szeto, H. H. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 171, 2029–2050 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Shen, B., Li, J. & Yang, B. NKG2D blockade significantly attenuates ischemia-reperfusion injury in a cardiac transplantation model. Transplant. Proc. 45, 2513–2516 (2013).

    CAS  PubMed  Google Scholar 

  254. von Lueder, T. G. & Krum, H. New medical therapies for heart failure. Nat. Rev. Cardiol. 12, 730–740 (2015).

    Google Scholar 

  255. Back, M. & Hansson, G. K. Anti-inflammatory therapies for atherosclerosis. Nat. Rev. Cardiol. 12, 199–211 (2015).

    PubMed  Google Scholar 

  256. Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondrial regulation of cell death: a phylogenetically conserved control. Microb. Cell 3, 101–108 (2016).

    PubMed  PubMed Central  Google Scholar 

  257. Toth, A. et al. Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion. Am. J. Physiol. Heart Circ. Physiol. 291, H52–H60 (2006).

    CAS  PubMed  Google Scholar 

  258. Kristen, A. V. et al. Inhibition of apoptosis by the intrinsic but not the extrinsic apoptotic pathway in myocardial ischemia-reperfusion. Cardiovasc. Pathol. 22, 280–286 (2013).

    CAS  PubMed  Google Scholar 

  259. Nakagawa, T. et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652–658 (2005).

    CAS  PubMed  Google Scholar 

  260. Baines, C. P. et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662 (2005). References 259 and 260 are among the first articles to provide robust genetic evidence in support of a non-redundant role for CypD in the regulation of MPT-driven regulated necrosis.

    CAS  PubMed  Google Scholar 

  261. Itani, H. A. et al. Mitochondrial cyclophilin D in vascular oxidative stress and hypertension. Hypertension 67, 1218–1227 (2016).

    CAS  PubMed  Google Scholar 

  262. Gordan, R., Fefelova, N., Gwathmey, J. K. & Xie, L. H. Involvement of mitochondrial permeability transition pore (mPTP) in cardiac arrhythmias: evidence from cyclophilin D knockout mice. Cell Calcium 60, 363–372 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. Zhou, H. Z. et al. Poly(ADP-ribose) polymerase-1 hyperactivation and impairment of mitochondrial respiratory chain complex I function in reperfused mouse hearts. Am. J. Physiol. Heart Circ. Physiol. 291, H714–H723 (2006).

    CAS  PubMed  Google Scholar 

  264. Zingarelli, B. et al. Absence of poly(ADP-ribose)polymerase-1 alters nuclear factor-kappa B activation and gene expression of apoptosis regulators after reperfusion injury. Mol. Med. 9, 143–153 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Wei, S. J. et al. Poly(ADP-ribose) polymerase 1 deficiency increases nitric oxide production and attenuates aortic atherogenesis through downregulation of arginase II. Clin. Exp. Pharmacol. Physiol. 44, 114–122 (2017).

    CAS  PubMed  Google Scholar 

  266. Zhang, T. et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat. Med. 22, 175–182 (2016). The authors characterize a CaMKII-dependent mechanism whereby necroptotic receptor-interacting serine/threonine-protein kinase 3 (RIPK3) activation feeds into MPT-driven regulated necrosis, thereby contributing to HF driven by ischaemia–reperfusion or doxorubicin administration.

    PubMed  Google Scholar 

  267. Oerlemans, M. I. et al. Targeting cell death in the reperfused heart: pharmacological approaches for cardioprotection. Int. J. Cardiol. 165, 410–422 (2013).

    PubMed  Google Scholar 

  268. Yaoita, H., Ogawa, K., Maehara, K. & Maruyama, Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 97, 276–281 (1998).

    CAS  PubMed  Google Scholar 

  269. Yang, W. et al. MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity. Br. J. Pharmacol. 140, 402–412 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Ono, M. et al. BH4 peptide derivative from Bcl-xL attenuates ischemia/reperfusion injury thorough anti-apoptotic mechanism in rat hearts. Eur. J. Cardiothorac. Surg. 27, 117–121 (2005).

    PubMed  Google Scholar 

  271. Hetz, C. et al. Bax channel inhibitors prevent mitochondrion-mediated apoptosis and protect neurons in a model of global brain ischemia. J. Biol. Chem. 280, 42960–42970 (2005).

    CAS  PubMed  Google Scholar 

  272. Liu, H. R. et al. Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion. Circulation 111, 90–96 (2005).

    CAS  PubMed  Google Scholar 

  273. Bhuiyan, M. S. & Fukunaga, K. Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart in vivo. Eur. J. Pharmacol. 557, 168–177 (2007).

    CAS  PubMed  Google Scholar 

  274. Jiang, X. et al. A small molecule that protects the integrity of the electron transfer chain blocks the mitochondrial apoptotic pathway. Mol. Cell 63, 229–239 (2016).

    CAS  PubMed  Google Scholar 

  275. Li, L. et al. Discovery of highly potent 2-sulfonyl-pyrimidinyl derivatives for apoptosis inhibition and ischemia treatment. ACS Med. Chem. Lett. 8, 407–412 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Schaller, S. et al. TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition. J. Pharmacol. Exp. Ther. 333, 696–706 (2010).

    CAS  PubMed  Google Scholar 

  277. Fancelli, D. et al. Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo. J. Med. Chem. 57, 5333–5347 (2014).

    CAS  PubMed  Google Scholar 

  278. Conrad, M., Angeli, J. P., Vandenabeele, P. & Stockwell, B. R. Regulated necrosis: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 15, 348–366 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. MITOCARE Study Group. Rationale and design of the ‘MITOCARE’ Study: a phase II, multicenter, randomized, double-blind, placebo-controlled study to assess the safety and efficacy of TRO40303 for the reduction of reperfusion injury in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Cardiology 123, 201–207 (2012).

    Google Scholar 

  280. Piot, C. et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N. Engl. J. Med. 359, 473–481 (2008).

    CAS  PubMed  Google Scholar 

  281. Cung, T. T. et al. Cyclosporine before PCI in patients with acute myocardial infarction. N. Engl. J. Med. 373, 1021–1031 (2015). This multicentre, double-blind, randomized clinical trial documents no cardioprotective role for cyclosporine A administered before PCI in patients with acute anterior ST-segment elevation MI.

    CAS  PubMed  Google Scholar 

  282. Ottani, F. et al. Cyclosporine A in reperfused myocardial infarction: the multicenter, controlled, open-label CYCLE Trial. J. Am. Coll. Cardiol. 67, 365–374 (2016).

    CAS  PubMed  Google Scholar 

  283. Le Lamer, S. et al. Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial. J. Transl Med. 12, 38 (2014).

    PubMed  PubMed Central  Google Scholar 

  284. Atar, D. et al. Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur. Heart J. 36, 112–119 (2015).

    CAS  PubMed  Google Scholar 

  285. van Gelder, T., van Schaik, R. H. & Hesselink, D. A. Pharmacogenetics and immunosuppressive drugs in solid organ transplantation. Nat. Rev. Nephrol. 10, 725–731 (2014).

    PubMed  Google Scholar 

  286. Choi, S. W. & Reddy, P. Current and emerging strategies for the prevention of graft-versus-host disease. Nat. Rev. Clin. Oncol. 11, 536–547 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. Hausenloy, D. J., Yellon, D. M., Mani-Babu, S. & Duchen, M. R. Preconditioning protects by inhibiting the mitochondrial permeability transition. Am. J. Physiol. Heart Circ. Physiol. 287, H841–H849 (2004).

    CAS  PubMed  Google Scholar 

  288. Ishii, H. et al. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 112, 1284–1288 (2005).

    CAS  PubMed  Google Scholar 

  289. Kitakaze, M. et al. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet 370, 1483–1493 (2007).

    CAS  PubMed  Google Scholar 

  290. Lee, H. C. et al. Effect of intra-coronary nicorandil administration prior to reperfusion in acute ST segment elevation myocardial infarction. Circ. J. 72, 1425–1429 (2008).

    CAS  PubMed  Google Scholar 

  291. Wojciechowska, A., Braniewska, A. & Kozar-Kaminska, K. MicroRNA in cardiovascular biology and disease. Adv. Clin. Exp. Med. 26, 865–874 (2017).

    PubMed  Google Scholar 

  292. Geiger, J. & Dalgaard, L. T. Interplay of mitochondrial metabolism and microRNAs. Cell. Mol. Life Sci. 74, 631–646 (2017).

    CAS  PubMed  Google Scholar 

  293. Das, S. et al. Divergent effects of miR-181 family members on myocardial function through protective cytosolic and detrimental mitochondrial microRNA targets. J. Am. Heart Assoc. 6, e004694 (2017).

    PubMed  PubMed Central  Google Scholar 

  294. Wang, K. et al. E2F1-regulated miR-30b suppresses Cyclophilin D and protects heart from ischemia/reperfusion injury and necrotic cell death. Cell Death Differ. 22, 743–754 (2015).

    CAS  PubMed  Google Scholar 

  295. Wang, K. et al. MicroRNA-2861 regulates programmed necrosis in cardiomyocyte by impairing adenine nucleotide translocase 1 expression. Free Radic. Biol. Med. 91, 58–67 (2016).

    CAS  PubMed  Google Scholar 

  296. Ucar, A. et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat. Commun. 3, 1078 (2012).

    PubMed  Google Scholar 

  297. Li, Z. et al. miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation. Cell Death Differ. 24, 1205–1213 (2017).

    CAS  PubMed  Google Scholar 

  298. Wang, K. et al. E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1. Nat. Commun. 6, 7619 (2015).

    CAS  PubMed  Google Scholar 

  299. Das, S. et al. miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo. PLoS ONE 9, e96820 (2014).

    PubMed  PubMed Central  Google Scholar 

  300. Tang, Y. et al. MicroRNA-150 protects the mouse heart from ischaemic injury by regulating cell death. Cardiovasc. Res. 106, 387–397 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  301. Jagannathan, R. et al. Translational regulation of the mitochondrial genome following redistribution of mitochondrial microRNA in the diabetic heart. Circ. Cardiovasc. Genet. 8, 785–802 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  302. Li, H. et al. MicroRNA-21 lowers blood pressure in spontaneous hypertensive rats by upregulating mitochondrial translation. Circulation 134, 734–751 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. Guan, X. et al. miR-106a promotes cardiac hypertrophy by targeting mitofusin 2. J. Mol. Cell. Cardiol. 99, 207–217 (2016).

    CAS  PubMed  Google Scholar 

  304. Wang, K. et al. NFAT4-dependent miR-324-5p regulates mitochondrial morphology and cardiomyocyte cell death by targeting Mtfr1. Cell Death Dis. 6, e2007 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  305. Long, B. et al. miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor. Free Radic. Biol. Med. 65, 371–379 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. Wang, J. X. et al. miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat. Med. 17, 71–78 (2011).

    PubMed  Google Scholar 

  307. Karunakaran, D. et al. Macrophage mitochondrial energy status regulates cholesterol efflux and is enhanced by anti-miR33 in atherosclerosis. Circ. Res. 117, 266–278 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  308. Rincon, M. Y., VandenDriessche, T. & Chuah, M. K. Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation. Cardiovasc. Res. 108, 4–20 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  309. Rusnak, F. & Mertz, P. Calcineurin: form and function. Physiol. Rev. 80, 1483–1521 (2000).

    CAS  PubMed  Google Scholar 

  310. Ikeda, G. et al. Nanoparticle-mediated targeting of cyclosporine a enhances cardioprotection against ischemia-reperfusion injury through inhibition of mitochondrial permeability transition pore opening. Sci. Rep. 6, 20467 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  311. Kelso, G. F. et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem. 276, 4588–4596 (2001).

    CAS  PubMed  Google Scholar 

  312. Jiang, J. et al. A mitochondria-targeted triphenylphosphonium-conjugated nitroxide functions as a radioprotector/mitigator. Radiat. Res. 172, 706–717 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  313. Galluzzi, L. et al. Methods to dissect mitochondrial membrane permeabilization in the course of apoptosis. Methods Enzymol. 442, 355–374 (2008).

    PubMed  Google Scholar 

  314. Horton, K. L., Stewart, K. M., Fonseca, S. B., Guo, Q. & Kelley, S. O. Mitochondria-penetrating peptides. Chem. Biol. 15, 375–382 (2008).

    CAS  PubMed  Google Scholar 

  315. Schmidt, O., Pfanner, N. & Meisinger, C. Mitochondrial protein import: from proteomics to functional mechanisms. Nat. Rev. Mol. Cell Biol. 11, 655–667 (2010).

    CAS  PubMed  Google Scholar 

  316. Barth, E., Stammler, G., Speiser, B. & Schaper, J. Ultrastructural quantitation of mitochondria and myofilaments in cardiac muscle from 10 different animal species including man. J. Mol. Cell. Cardiol. 24, 669–681 (1992).

    CAS  PubMed  Google Scholar 

  317. Izzo, V., Bravo-San Pedro, J. M., Sica, V., Kroemer, G. & Galluzzi, L. Mitochondrial permeability transition: new findings and persisting uncertainties. Trends Cell Biol. 26, 655–667 (2016).

    CAS  PubMed  Google Scholar 

  318. Bonora, M. et al. Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12, 674–683 (2013). This study is the first demonstration that the c subunit of the F 1 F o ATP synthase is mechanistically involved in MPT-driven regulated necrosis, at least in some experimental models.

    CAS  PubMed  PubMed Central  Google Scholar 

  319. Galluzzi, L. et al. No death without life: vital functions of apoptotic effectors. Cell Death Differ. 15, 1113–1123 (2008).

    CAS  PubMed  Google Scholar 

  320. Hao, Z. et al. Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis. Cell 121, 579–591 (2005). The authors elegantly uncouple the vital and lethal roles of cytochrome c by generating a mutant cytochrome c that functions normally within the respiratory chain but fails to activate apoptotic protease-activating factor 1 (APAF1).

    CAS  PubMed  Google Scholar 

  321. Zhivotovsky, B., Galluzzi, L., Kepp, O. & Kroemer, G. Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery. Cell Death Differ. 16, 1419–1425 (2009).

    CAS  PubMed  Google Scholar 

  322. De Grassi, A., Lanave, C. & Saccone, C. Evolution of ATP synthase subunit c and cytochrome c gene families in selected Metazoan classes. Gene 371, 224–233 (2006).

    PubMed  Google Scholar 

  323. Mutlu-Turkoglu, U. et al. Increased plasma malondialdehyde and protein carbonyl levels and lymphocyte DNA damage in patients with angiographically defined coronary artery disease. Clin. Biochem. 38, 1059–1065 (2005).

    PubMed  Google Scholar 

  324. Aryal, B., Jeong, J. & Rao, V. A. Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity. Proc. Natl Acad. Sci. USA 111, 2011–2016 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  325. Ruiz, M. et al. Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond. Am. J. Physiol. Heart Circ. Physiol. 313, H768–H781 (2017).

    CAS  PubMed  Google Scholar 

  326. Stotland, A. & Gottlieb, R. A. α-MHC MitoTimer mouse: in vivo mitochondrial turnover model reveals remarkable mitochondrial heterogeneity in the heart. J. Mol. Cell. Cardiol. 90, 53–58 (2016).

    CAS  PubMed  Google Scholar 

  327. Wilson, R. J. et al. Conditional MitoTimer reporter mice for assessment of mitochondrial structure, oxidative stress, and mitophagy. Mitochondrion https://doi.org/10.1016/j.mito.2017.12.008 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  328. Li, J., Lu, J. & Zhou, Y. Mitochondrial-targeted molecular imaging in cardiac disease. BioMed. Res. Int. 2017, 5246853 (2017).

    PubMed  PubMed Central  Google Scholar 

  329. Sack, M. N. & Murphy, E. The role of comorbidities in cardioprotection. J. Cardiovasc. Pharmacol. Ther. 16, 267–272 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  330. Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73 (2015).

    CAS  PubMed  Google Scholar 

  331. Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017).

    CAS  PubMed  Google Scholar 

  332. Galluzzi, L., Lopez-Soto, A., Kumar, S. & Kroemer, G. Caspases connect cell-death signaling to organismal homeostasis. Immunity 44, 221–231 (2016).

    CAS  PubMed  Google Scholar 

  333. Dean, J., Cruz, S. D., Mehta, P. K. & Merz, C. N. Coronary microvascular dysfunction: sex-specific risk, diagnosis, and therapy. Nat. Rev. Cardiol. 12, 406–414 (2015).

    PubMed  Google Scholar 

  334. Pagidipati, N. J. & Peterson, E. D. Acute coronary syndromes in women and men. Nat. Rev. Cardiol. 13, 471–480 (2016).

    PubMed  Google Scholar 

  335. Hu, X. X. et al. The cardioprotective effect of vitamin E (alpha-tocopherol) is strongly related to age and gender in mice. PLoS ONE 10, e0137405 (2015).

    PubMed  PubMed Central  Google Scholar 

  336. Baines, C. P., Kaiser, R. A., Sheiko, T., Craigen, W. J. & Molkentin, J. D. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat. Cell Biol. 9, 550–555 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  337. Galluzzi, L. & Kroemer, G. Mitochondrial apoptosis without VDAC. Nat. Cell Biol. 9, 487–489 (2007).

    CAS  PubMed  Google Scholar 

  338. Kokoszka, J. E. et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427, 461–465 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  339. Gustafsson, A. B. & Gottlieb, R. A. Heart mitochondria: gates of life and death. Cardiovasc. Res. 77, 334–343 (2008).

    CAS  PubMed  Google Scholar 

  340. Green, D. R., Galluzzi, L. & Kroemer, G. Cell biology. Metabolic control of cell death. Science 345, 1250256 (2014).

    PubMed  PubMed Central  Google Scholar 

  341. Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158–167 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  342. Schwarz, K. et al. The breathing heart — mitochondrial respiratory chain dysfunction in cardiac disease. Int. J. Cardiol. 171, 134–143 (2014).

    PubMed  Google Scholar 

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Acknowledgements

The authors apologize to the authors of several high-quality articles on mitochondria as a therapeutic target for cardiovascular disorders that could not be discussed and cited owing to space limitations. M.R.W. is supported by a Polish National Science Centre grant (UMO-2014/15/B/NZ1/00490). D.A.S. receives support from the Glenn Foundation for Medical Research, the Sinclair Gift Fund, and the US NIH/National Institute on Aging (R01 AG028730 and R01 DK100263). G.K. receives support from the Ligue Nationale contre le Cancer Comité de Charente-Maritime (équipe labellisée); the Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; the Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), the Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); the European Research Council (ERC); Fondation Carrefour; the Institut National du Cancer (INCa); INSERM (HTE); the Institut Universitaire de France; the LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). P.P. is grateful to Camilla degli Scrovegni for continuous support; P.P. receives support from the Italian Ministry of Education, the University and Research; Telethon (GGP15219/B); the Italian Association for Cancer Research (AIRC; IG-18624); and by local funds from the University of Ferrara (Ferrara, Italy). L.G. is supported by a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA) and by donations from Sotio a.s. (Prague, Czech Republic), Phosplatin (New York, NY, USA), and the Luke Heller TECPR2 Foundation (Boston, MA, USA).

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Nature Reviews Cardiology thanks R. Gottlieb, M. Hirschey, M. Sack, and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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M.B., M.R.W., and L.G. researched data for the article and wrote the manuscript. D.A.S., G.K., P.P., and L.G. reviewed and/or edited the manuscript before submission. All authors made substantial contributions to discussion of the content.

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Correspondence to Paolo Pinton or Lorenzo Galluzzi.

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D.A.S. is a consultant to and inventor on patents licensed to CohBar, GlaxoSmithKline, Jumpstart Fertility, Liberty Biosecurity, Life Biosciences, and MetroBiotech. The other authors declare no competing interests.

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Glossary

Regulated cell death

(RCD). A form of cell death that relies on the activation of a genetically encoded machinery and which, therefore, can be retarded or accelerated with specific pharmacological or genetic interventions.

Autophagy

Evolutionarily conserved cellular process that culminates with the lysosomal degradation of ectopic, supernumerary, dysfunctional, or potentially dangerous cytoplasmic entities (of endogenous or exogenous derivation).

β-Oxidation

Biochemical pathway whereby fatty acids are converted into acetyl-CoA, which enters the TCA cycle, and NADH and FADH2, which fuel oxidative phosphorylation.

Ketolysis

Biochemical pathway whereby ketone bodies are converted into acetyl-CoA, which enters the TCA cycle, and NADH, which fuels oxidative phosphorylation.

Folate cycle

Biochemical pathway catalysing the cyclic conversion of tetrahydrofolate, 10-formyl-tetrahydrofolate (which feeds into purine synthesis), 5,10-methylenetetrahydrofolate, and 5-methyl-tetrahydrofolate (which feeds into methionine metabolism).

Mitochondrial permeability transition

(MPT). Rapid loss of the ionic barrier function of the inner mitochondrial membrane, culminating in mitochondrial breakdown and regulated necrosis.

Transferrin

Iron-binding plasma glycoprotein that controls the level of free iron ions in biological fluids.

Cerebral cavernous malformations

Cerebrovascular disease characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral haemorrhages.

Histone deacetylase inhibitor

Member of a fairly new class of targeted anticancer agents that operate by derepressing histone acetylation, resulting in the epigenetic reconfiguration of multiple transcriptional modules.

Necroptosis

Form of RCD that depends on mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and, at least in some settings, the kinase activity of the RIPK3 homologue RIPK1.

Ferroptosis

Iron-dependent form of RCD that obligatorily relies on lipid peroxidation and is tonically inhibited by glutathione peroxidase 4 (GPx4).

Damage-associated molecular patterns

(DAMPs). Endogenous molecules that exert potent immunomodulatory functions upon binding to cellular receptors that evolved to control microbial pathogens.

Inflammasome

Supramolecular complex containing caspase 1 (CASP1), which, among other functions, catalyses the proteolytic processing of IL-1β and IL-18, thereby enabling their release in a bioactive form.

γδ T lymphocytes

Small subsets of T cells expressing a rather invariant variant of the T cell receptor and mostly operating at the interface between innate and adaptive immunity.

Eicosanoids

Large family of arachidonic acid derivatives involved in the regulation of multiple biological processes, including the recruitment and activation of immune cells.

Apoptosis

Form of RCD initiated by extracellular or intracellular cues that is precipitated by the sequential activation of various members of the caspase protein family.

Parthanatos

Necrotic variant of RCD driven by PARP1 hyperactivation and precipitated by the consequent bioenergetic catastrophe coupled to enzymatic DNA degradation.

microRNAs

(miRNAs). Small non-coding RNA molecules that regulate the expression of target genes at the transcriptional or post-transcriptional level.

Nanoparticle

Particle of 1–100 nm in size surrounded by an interfacial layer consisting of ions, inorganic molecules, or organic molecules that determines the biological and biophysical properties of the particle.

Mitochondrial transmembrane potential

(Δψm). Electrochemical gradient built across the inner mitochondrial membrane by the respiratory chain. The Δψm drives multiple mitochondrial functions, including ATP synthesis and protein transport.

Carbonylation

Term generally referring to the metal-catalysed oxidation (primary carbonylation) or addition of reactive aldehydes (secondary carbonylation) to amino acid side chains.

Pharmacological audit trail

Rational framework to guide the development of novel therapeutic agents that involves assessing the risk of failure at any specific stage.

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Bonora, M., Wieckowski, M.R., Sinclair, D.A. et al. Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles. Nat Rev Cardiol 16, 33–55 (2019). https://doi.org/10.1038/s41569-018-0074-0

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