Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of mitochondrial fission in cardiovascular health and disease

Nature Reviews Cardiology volume 19, pages 723–736 (2022)Cite this article

Subjects

Abstract

Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial network is essential for cardiovascular function and adaptation to pathological stressors. Mitochondria undergo fission or fusion in response to various environmental cues, and these dynamic changes are vital for mitochondrial function and health. In particular, mitochondrial fission is closely coordinated with the cell cycle and is linked to changes in mitochondrial respiration and membrane permeability. Another key function of fission is the segregation of damaged mitochondrial components for degradation by mitochondrial autophagy (mitophagy). Mitochondrial fission is induced by the large GTPase dynamin-related protein 1 (DRP1) and is subject to sophisticated regulation. Activation requires various post-translational modifications of DRP1, actin polymerization and the involvement of other organelles such as the endoplasmic reticulum, Golgi apparatus and lysosomes. A decrease in mitochondrial fusion can also shift the balance towards mitochondrial fission. Although mitochondrial fission is necessary for cellular homeostasis, this process is often aberrantly activated in cardiovascular disease. Indeed, strong evidence exists that abnormal mitochondrial fission directly contributes to disease development. In this Review, we compare the physiological and pathophysiological roles of mitochondrial fission and discuss the therapeutic potential of preventing excessive mitochondrial fission in the heart and vasculature.

Key points

  • Mitochondria are involved in regulating many important cellular processes, including metabolism, ATP generation, immune response and activation of cell death pathways.

  • Mitochondria are dynamic and undergo changes in morphology in response to various environmental cues, which affects organelle function.

  • Mitochondrial fission is subject to sophisticated regulation, and activation involves various post-translational modifications of dynamin-related protein 1 (DRP1), actin polymerization, and the involvement of other organelles.

  • Although mitochondrial fission is crucial for cardiac homeostasis, strong evidence indicates that dysregulation of DRP1-mediated fission contributes to the development of several cardiovascular pathologies.

  • Targeting proteins that regulate mitochondrial dynamics has strong therapeutic potential for cardiovascular disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structure and function of DRP1 in mitochondrial fission.
Fig. 2: Interorganelle contacts promote mitochondrial fission.
Fig. 3: Distinct mitochondrial fission subtypes produce divergent fates.
Fig. 4: Sustained mitochondrial fission promotes cardiovascular pathophysiology.

Similar content being viewed by others

References

  1. Bock, F. J. & Tait, S. W. G. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell Biol. 21, 85–100 (2020).

    Article  CAS  PubMed  Google Scholar 

  2. Frank, S. et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Hoque, A. et al. Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells. Cell Death Discov. 4, 39 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gustafsson, A. B. & Dorn, G. W. II Evolving and expanding the roles of mitophagy as a homeostatic and pathogenic process. Physiol. Rev. 99, 853–892 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Taguchi, N., Ishihara, N., Jofuku, A., Oka, T. & Mihara, K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J. Biol. Chem. 282, 11521–11529 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Lewis, S. C., Uchiyama, L. F. & Nunnari, J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353, 261 (2016).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pennanen, C. et al. Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. J. Cell Sci. 127, 2659–2671 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Rogers, M. A. et al. Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion. Cardiovasc. Res. 117, 2340–2353 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kalia, R. et al. Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature 558, 401–405 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fröhlich, C. et al. Structural insights into oligomerization and mitochondrial remodelling of dynamin 1-like protein. EMBO J. 32, 1280–1292 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mozdy, A. D., McCaffery, J. M. & Shaw, J. M. Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J. Cell Biol. 151, 367–380 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. James, D. I., Parone, P. A., Mattenberger, Y. & Martinou, J.-C. hFis1, a novel component of the mammalian mitochondrial fission machinery. J. Biol. Chem. 278, 36373–36379 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Yoon, Y., Krueger, E. W., Oswald, B. J. & McNiven, M. A. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol. Cell Biol. 23, 5409–5420 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Loson, O. C., Song, Z., Chen, H. & Chan, D. C. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol. Biol. Cell 24, 659–667 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee, Y.-j, Jeong, S.-Y., Karbowski, M., Smith, C. L. & Youle, R. J. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell 15, 5001–5011 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Otera, H. et al. Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J. Cell Biol. 191, 1141–1158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shen, Q. et al. Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Mol. Biol. Cell 25, 145–159 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kleele, T. et al. Distinct fission signatures predict mitochondrial degradation or biogenesis. Nature 593, 435–439 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Varuzhanyan, G. et al. Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation. Development 148, 199686 (2021).

    Article  Google Scholar 

  24. Osellame, L. D. et al. Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission. J. Cell Sci. 129, 2170–2181 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Moyzis, A. G. et al. Mcl-1-mediated mitochondrial fission protects against stress but impairs cardiac adaptation to exercise. J. Mol. Cell Cardiol. 146, 109–120 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee, Y., Lee, H.-Y., Hanna, R. A. & Gustafsson, Å. B. Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 301, H1924–H1931 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen, M. et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy 12, 689–702 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ishihara, N. et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat. Cell Biol. 11, 958–966 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Wakabayashi, J. et al. The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell Biol. 186, 805–816 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ishihara, T. et al. Dynamics of mitochondrial DNA nucleoids regulated by mitochondrial fission is essential for maintenance of homogeneously active mitochondria during neonatal heart development. Mol. Cell Biol. 35, 211–223 (2015).

    Article  PubMed  Google Scholar 

  31. Kageyama, Y. et al. Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J. 33, 2798–2813 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Song, M., Mihara, K., Chen, Y., Scorrano, L. & Dorn, G. W. II Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab. 21, 273–286 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Galloway, C. A. et al. Transgenic control of mitochondrial fission induces mitochondrial uncoupling and relieves diabetic oxidative stress. Diabetes 61, 2093–2104 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, H. et al. Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy. J. Cell Biol. 211, 795–805 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gao, S. & Hu, J. Mitochondrial fusion: the machineries in and out. Trends Cell Biol. 31, 62–74 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Chen, H. et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 160, 189–200 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Papanicolaou, K. N. et al. Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ. Res. 111, 1012–1026 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Davies, V. J. et al. Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum. Mol. Genet. 16, 1307–1318 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Wai, T. et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350, aad0116 (2015).

    Article  PubMed  Google Scholar 

  41. 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 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Saito, T. et al. An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. J. Clin. Invest. 129, 802–819 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Han, H. et al. PINK 1 phosphorylates Drp1S616 to regulate mitophagy-independent mitochondrial dynamics. EMBO Rep. 21, e48686 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cribbs, J. T. & Strack, S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 8, 939–944 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cereghetti, G. et al. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc. Natl Acad. Sci. USA 105, 15803–15808 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yu, R. et al. The phosphorylation status of Ser-637 in dynamin-related protein 1 (Drp1) does not determine Drp1 recruitment to mitochondria. J. Biol. Chem. 294, 17262–17277 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jhun, B. S. et al. Protein kinase D activation induces mitochondrial fragmentation and dysfunction in cardiomyocytes. J. Physiol. 596, 827–855 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang, W. et al. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab. 15, 186–200 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Valera-Alberni, M. et al. Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation. Cell Rep. 36, 109565 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Guo, C., Wilkinson, K. A., Evans, A. J., Rubin, P. P. & Henley, J. M. SENP3-mediated deSUMOylation of Drp1 facilitates interaction with Mff to promote cell death. Sci. Rep. 7, 43811 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Figueroa-Romero, C. et al. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J. 23, 3917–3927 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Guo, C. et al. SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. EMBO J. 32, 1514–1528 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hu, Q. et al. Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction. Circ. Res. 126, 456–470 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gawlowski, T. et al. Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-beta-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J. Biol. Chem. 287, 30024–30034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lee, D. S. & Kim, J. E. PDI-mediated S-nitrosylation of DRP1 facilitates DRP1-S616 phosphorylation and mitochondrial fission in CA1 neurons. Cell Death Dis. 9, 869 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Cho, D. H. et al. S-Nitrosylation of Drp1 mediates β-amyloid-related mitochondrial fission and neuronal injury. Science 324, 102–105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bossy, B. et al. S-Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer’s disease. J. Alzheimers Dis. 20, S513–S526 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Rizza, S. et al. S-Nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proc. Natl Acad. Sci. USA 115, E3388–E3397 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wasiak, S., Zunino, R. & McBride, H. M. Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J. Cell Biol. 177, 439–450 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Prudent, J. et al. MAPL SUMOylation of Drp1 stabilizes an ER/mitochondrial platform required for cell death. Mol. Cell 59, 941–955 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Bertero, E. & Maack, C. Metabolic remodelling in heart failure. Nat. Rev. Cardiol. 15, 457–470 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Hess, D. T. & Stamler, J. S. Regulation by S-nitrosylation of protein post-translational modification. J. Biol. Chem. 287, 4411–4418 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Farah, C., Michel, L. Y. & Balligand, J.-L. Nitric oxide signalling in cardiovascular health and disease. Nat. Rev. Cardiol. 15, 292–316 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. Prinz, W. A., Toulmay, A. & Balla, T. The functional universe of membrane contact sites. Nat. Rev. Mol. Cell Biol. 21, 7–24 (2020).

    Article  CAS  PubMed  Google Scholar 

  66. Friedman, J. R. et al. ER tubules mark sites of mitochondrial division. Science 334, 358–362 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ji, W. K. et al. Receptor-mediated Drp1 oligomerization on endoplasmic reticulum. J. Cell Biol. 216, 4123–4139 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Korobova, F., Ramabhadran, V. & Higgs, H. N. An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339, 464–467 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Ji, W.-k, Hatch, A. L., Merrill, R. A., Strack, S. & Higgs, H. N. Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. eLife 4, e11553 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Moore, A. S., Wong, Y. C., Simpson, C. L. & Holzbaur, E. L. Dynamic actin cycling through mitochondrial subpopulations locally regulates the fission–fusion balance within mitochondrial networks. Nat. Commun. 7, 12886 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ramonett, A. et al. Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport. Mol. Biol. Cell 33, ar4 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nagashima, S. et al. Golgi-derived PI(4)P-containing vesicles drive late steps of mitochondrial division. Science 367, 1366–1371 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Wong, Y. C., Ysselstein, D. & Krainc, D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554, 382–386 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Boutry, M. & Kim, P. K. ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division. Nat. Commun. 12, 5354 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yu, W. et al. TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury. Theranostics 10, 11244 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dong, R. et al. Endosome-ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell 166, 408–423 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cho, B. et al. Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division. Nat. Commun. 8, 15754 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Chakrabarti, R. et al. INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division. J. Cell Biol. 217, 251–268 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Qin, Y. et al. Mitochondrial fusion mediated by fusion promotion and fission inhibition directs adult mouse heart function toward a different direction. FASEB J. 34, 663–675 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Favaro, G. et al. DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat. Commun. 10, 2576 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Pangou, E. et al. A PKD-MFF signaling axis couples mitochondrial fission to mitotic progression. Cell Rep. 35, 109129 (2021).

    Article  CAS  PubMed  Google Scholar 

  82. Kashatus, D. F. et al. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat. Cell Biol. 13, 1108–1115 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gao, Q.-Y. et al. Mitochondrial fission and mitophagy reciprocally orchestrate cardiac fibroblasts activation. Front. Cell Dev. Biol. 8, 1741 (2021).

    Article  Google Scholar 

  84. Zhang, X. et al. Involvement of mitochondrial fission in calcium sensing receptor-mediated vascular smooth muscle cells proliferation during hypertension. Biochem. Biophys. Res. Commun. 495, 454–460 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Chen, K.-H. et al. Epigenetic dysregulation of the dynamin-related protein 1 binding partners MiD49 and MiD51 increases mitotic mitochondrial fission and promotes pulmonary arterial hypertension: mechanistic and therapeutic implications. Circulation 138, 287–304 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ban-Ishihara, R., Ishihara, T., Sasaki, N., Mihara, K. & Ishihara, N. Dynamics of nucleoid structure regulated by mitochondrial fission contributes to cristae reformation and release of cytochrome c. Proc. Natl Acad. Sci. USA 110, 11863–11868 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–446 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cho, H. M. et al. Drp1-Zip1 interaction regulates mitochondrial quality surveillance system. Mol. Cell 73, 364–376.e8 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Aishwarya, R. et al. Pleiotropic effects of mdivi-1 in altering mitochondrial dynamics, respiration, and autophagy in cardiomyocytes. Redox Biol. 36, 101660 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hammerling, B. C. et al. A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance. Nat. Commun. 8, 14050 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yamashita, S. I. et al. Mitochondrial division occurs concurrently with autophagosome formation but independently of Drp1 during mitophagy. J. Cell Biol. 215, 649–665 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang, H. et al. A novel fission-independent role of dynamin-related protein 1 in cardiac mitochondrial respiration. Cardiovasc. Res. 113, 160–170 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Vercellino, I. & Sazanov, L. A. The assembly, regulation and function of the mitochondrial respiratory chain. Nat. Rev. Mol. Cell Biol. 23, 141–161 (2021).

    Article  PubMed  Google Scholar 

  98. Zepeda, R. et al. Drp1 loss-of-function reduces cardiomyocyte oxygen dependence protecting the heart from ischemia-reperfusion injury. J. Cardiovasc. Pharmacol. 63, 477–487 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Deng, Y. et al. AMPKα2 overexpression reduces cardiomyocyte ischemia-reperfusion injury through normalization of mitochondrial dynamics. Front. Cell Dev. Biol. 8, 833 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Alam, S. et al. Aberrant mitochondrial fission is maladaptive in desmin mutation-induced cardiac proteotoxicity. J. Am. Heart Assoc. 7, e009289 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Joshi, A., Ebert, A., Haileselassie, B. & Mochly-Rosen, D. Drp1/Fis1-mediated mitochondrial fragmentation leads to lysosomal dysfunction in cardiac models of Huntington’s disease. J. Mol. Cell Cardiol. 127, 125–133 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Bekhite, M. et al. The role of ceramide accumulation in human induced pluripotent stem cell-derived cardiomyocytes on mitochondrial oxidative stress and mitophagy. Free Radic. Biol. Med. 167, 66–80 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. Tsushima, K. et al. Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission. Circ. Res. 122, 58–73 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Haileselassie, B. et al. Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy. J. Mol. Cell Cardiol. 130, 160–169 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wang, Y., Yu, W., Shi, C. & Hu, P. Crocetin attenuates sepsis-induced cardiac dysfunction via regulation of inflammatory response and mitochondrial function. Front. Physiol. 11, 514 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Kim, Y.-M. et al. Redox regulation of mitochondrial fission protein Drp1 by protein disulfide isomerase limits endothelial senescence. Cell Rep. 23, 3565–3578 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kim, D., Sankaramoorthy, A. & Roy, S. Downregulation of Drp1 and Fis1 inhibits mitochondrial fission and prevents high glucose-induced apoptosis in retinal endothelial cells. Cells 9, 1662 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  108. Zhu, Y. et al. Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy. Apoptosis 25, 321–340 (2020).

    Article  CAS  PubMed  Google Scholar 

  109. Karbowski, M. et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J. Cell Biol. 159, 931–938 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Oettinghaus, B. et al. DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress. Biochim. Biophys. Acta 1857, 1267–1276 (2016).

    Article  CAS  PubMed  Google Scholar 

  111. Cassidy-Stone, A. et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev. Cell 14, 193–204 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jenner, A. et al. DRP1 interacts directly with BAX to induce its activation and apoptosis. EMBO J. https://doi.org/10.15252/embj.2021108587 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Otera, H., Miyata, N., Kuge, O. & Mihara, K. Drp1-dependent mitochondrial fission via MiD49/51 is essential for apoptotic cristae remodeling. J. Cell Biol. 212, 531–544 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bauer, T. M. & Murphy, E. Role of mitochondrial calcium and the permeability transition pore in regulating cell death. Circ. Res. 126, 280–293 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Duan, C. et al. Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2. Cell Death Dis. 12, 1050 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhou, H. et al. Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening. J. Am. Heart Assoc. 6, e005328 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Zhou, H. et al. Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC 1-HK 2-mPTP-mitophagy axis. J. Pineal Res. 63, e12413 (2017).

    Article  PubMed Central  Google Scholar 

  118. Touvier, T. et al. Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation. Cell Death Dis. 6, e1663 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Smirnova, E., Griparic, L., Shurland, D.-L. & Van Der Bliek, A. M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245–2256 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Campello, S. et al. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J. Exp. Med. 203, 2879–2886 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Simula, L. et al. Drp1 controls effective T cell immune-surveillance by regulating T cell migration, proliferation, and cMyc-dependent metabolic reprogramming. Cell Rep. 25, 3059–3073.e10 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chang, C.-H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Basit, F., Mathan, T., Sancho, D. & de Vries, I. J. M. Human dendritic cell subsets undergo distinct metabolic reprogramming for immune response. Front. Immunol. 9, 2489 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Gao, Z. et al. Mitochondrial dynamics controls anti-tumour innate immunity by regulating CHIP-IRF1 axis stability. Nat. Commun. 8, 1805 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Wang, Y. et al. Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages. Cell 171, 331–345.e22 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  128. Sabbah, H. N., Gupta, R. C., Singh-Gupta, V., Zhang, K. & Lanfear, D. E. Abnormalities of mitochondrial dynamics in the failing heart: normalization following long-term therapy with elamipretide. Cardiovasc. Drugs Ther. 32, 319–328 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hsiao, Y. T. et al. Cardiac mitofusin-1 is reduced in non-responding patients with idiopathic dilated cardiomyopathy. Sci. Rep. 11, 6722 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Moore, T. M. et al. The impact of exercise on mitochondrial dynamics and the role of Drp1 in exercise performance and training adaptations in skeletal muscle. Mol. Metab. 21, 51–67 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. He, W. et al. Exercise enhanced cardiac function in mice with radiation-induced heart disease via the FNDC5/irisin-dependent mitochondrial turnover pathway. Front. Physiol. 12, 739485 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387–407 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Qi, J. et al. Mitochondrial fission is required for angiotensin II-induced cardiomyocyte apoptosis mediated by a Sirt1-p53 signaling pathway. Front. Pharmacol. 9, 176 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Chang, Y.-W. et al. Quantitative phosphoproteomic study of pressure-overloaded mouse heart reveals dynamin-related protein 1 as a modulator of cardiac hypertrophy. Mol. Cell Proteom. 12, 3094–3107 (2013).

    Article  CAS  Google Scholar 

  135. Miranda-Silva, D. et al. Mitochondrial reversible changes determine diastolic function adaptations during myocardial (reverse) remodeling. Circ. Heart Fail. 13, e006170 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Nishimura, A. et al. Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. Sci. Signal. 11, eaat5185 (2018).

    Article  PubMed  Google Scholar 

  138. Zhou, H. et al. NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic. Res. Cardiol. 113, 23 (2018).

    Article  PubMed  Google Scholar 

  139. Hinderer, S. & Schenke-Layland, K. Cardiac fibrosis–a short review of causes and therapeutic strategies. Adv. Drug Deliv. Rev. 146, 77–82 (2019).

    Article  CAS  PubMed  Google Scholar 

  140. Tian, L. et al. Increased Drp1-mediated mitochondrial fission promotes proliferation and collagen production by right ventricular fibroblasts in experimental pulmonary arterial hypertension. Front. Physiol. 9, 828 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Tseng, H.-C., Lin, C.-C., Hsiao, L.-D. & Yang, C.-M. Lysophosphatidylcholine-induced mitochondrial fission contributes to collagen production in human cardiac fibroblasts. J. Lipid Res. 60, 1573–1589 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hasan, P. et al. Mitochondrial fission protein, dynamin-related protein 1, contributes to the promotion of hypertensive cardiac hypertrophy and fibrosis in Dahl-salt sensitive rats. J. Mol. Cell Cardiol. 121, 103–106 (2018).

    Article  CAS  PubMed  Google Scholar 

  143. Rogers, M. A. et al. Dynamin-related protein 1 inhibition attenuates cardiovascular calcification in the presence of oxidative stress. Circ. Res. 121, 220–233 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Durham, A. L., Speer, M. Y., Scatena, M., Giachelli, C. M. & Shanahan, C. M. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc. Res. 114, 590–600 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Cui, L., Li, Z., Chang, X., Cong, G. & Hao, L. Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrial fission. Vasc. Pharmacol. 88, 21–29 (2017).

    Article  CAS  Google Scholar 

  146. Buijs, R. V. et al. Calcification as a risk factor for rupture of abdominal aortic aneurysm. Eur. J. Vasc. Endovasc. Surg. 46, 542–548 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Cooper, H. A. et al. Targeting mitochondrial fission as a potential therapeutic for abdominal aortic aneurysm. Cardiovasc. Res. 117, 971–982 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Huang, G. et al. Targeting HSP90 attenuates angiotensin II-induced adventitial remodelling via suppression of mitochondrial fission. Cardiovasc. Res. 116, 1071–1084 (2020).

    CAS  PubMed  Google Scholar 

  149. Rijzewijk, L. J. et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 52, 1793–1799 (2008).

    Article  PubMed  Google Scholar 

  150. Parra, V. et al. Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death. Biochim. Biophys. Acta 1832, 1334–1344 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wu, Q.-R. et al. High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy. Cell Death Dis. 12, 216 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wang, L. et al. Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. Diabetologia 58, 2371–2380 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. Umezu, R. et al. Macrophage (Drp1) dynamin-related protein 1 accelerates intimal thickening after vascular injury. Arterioscler. Thromb. Vasc. Biol. 40, e214–e226 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Wang, L. et al. Decreasing mitochondrial fission diminishes vascular smooth muscle cell migration and ameliorates intimal hyperplasia. Cardiovasc. Res. 106, 272–283 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Forrester, S. J. et al. Mitochondrial fission mediates endothelial inflammation. Hypertension 76, 267–276 (2020).

    Article  CAS  PubMed  Google Scholar 

  156. Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Miyao, M. et al. Involvement of senescence and mitochondrial fission in endothelial cell pro-inflammatory phenotype induced by angiotensin II. Int. J. Mol. Sci. 21, 3112 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  158. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wu, D. et al. Identification of novel dynamin-related protein 1 (Drp1) GTPase inhibitors: therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia-reperfusion injury. FASEB J. 34, 1447–1464 (2020).

    Article  CAS  PubMed  Google Scholar 

  160. Ong, S.-B. et al. Targeting mitochondrial fission using Mdivi-1 in a clinically relevant large animal model of acute myocardial infarction: a pilot study. Int. J. Mol. Sci. 20, 3972 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  161. Kornfeld, O. S. et al. Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo. Sci. Rep. 8, 14034 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Wang, Q. et al. Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes 66, 193–205 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Zhou, H. et al. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 15, 335–346 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. Kalkhoran, S. B. et al. Hydralazine protects the heart against acute ischemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission. Cardiovasc. Res. 118, 282–294 (2021).

    Article  PubMed Central  Google Scholar 

  165. Yu, L. M. et al. Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury by improving mitochondrial quality control: role of SIRT6. J. Pineal Res. 70, e12698 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Chen, W. R. et al. Melatonin attenuates vascular calcification by inhibiting mitochondria fission via an AMPK/Drp1 signalling pathway. J. Cell Mol. Med. 24, 6043–6054 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lee, T.-L. et al. Vitamin D attenuates ischemia/reperfusion-induced cardiac injury by reducing mitochondrial fission and mitophagy. Front. Pharmacol. 11, 604700 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Liang, X. et al. Mitophagy inhibitor liensinine suppresses doxorubicin-induced cardiotoxicity through inhibition of Drp1-mediated maladaptive mitochondrial fission. Pharmacol. Res. 157, 104846 (2020).

    Article  CAS  PubMed  Google Scholar 

  169. Singh, A., Faccenda, D. & Campanella, M. Pharmacological advances in mitochondrial therapy. eBioMedicine 65, 103244 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.M.Q. is supported by a postdoctoral fellowship from the AHA (#830983). Å.B.G. is supported by NIH grants R01HL138560, R01HL132300, R01HL155281 and R01HL157265.

Author information

Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA

    Justin M. Quiles & Åsa B. Gustafsson

Authors
  1. Justin M. Quiles
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Åsa B. Gustafsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed substantially to all aspects of the article.

Corresponding author

Correspondence to Åsa B. Gustafsson.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cardiology thanks Sergio Lavandero, Jun Ren and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quiles, J.M., Gustafsson, Å.B. The role of mitochondrial fission in cardiovascular health and disease. Nat Rev Cardiol 19, 723–736 (2022). https://doi.org/10.1038/s41569-022-00703-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-022-00703-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing