Key Points
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Over the past decade, more evidence has accumulated regarding the involvement of mitochondrial dysfunction in the pathogenesis of type 2 diabetes, sarcopaenia, Parkinson's disease, cancer and, to a lesser extent, Alzheimer's disease. Modulating mitochondrial function has therefore emerged as an attractive strategy to treat both inherited mitochondrial diseases and age-related diseases associated with mitochondrial dysfunction, and spurred active drug discovery efforts in this area.
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Several pathways are important to maintain and/or restore mitochondrial function and hence have potential therapeutic value. The best-characterized pathway is that involving the regulation of mitochondrial function by sensors of the nutrient or energy status, such as the pathway involving AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) and their downstream effectors. Other key pathways that regulate mitochondrial function, such as fusion and/or fission, mitophagy and the mitochondrial unfolded protein response, have been recently added to the equation, but there are very few compounds available to specifically modulate these pathways.
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Most of the compounds that modulate mitochondrial function have been identified via target-based screens, including compounds that bind to and modulate G-protein-coupled receptors (such as G protein-coupled bile acid receptor 1), nuclear receptors and other transcription factors (such as peroxisome proliferator-activated receptors and oestrogen-related receptors), kinases (such as AMPK) and enzymes (such as SIRT1).
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Recently, several phenotypic screening strategies have enabled the identification of novel chemical entities that modulate more global phenotypes, such as fusion and mitochondrial biogenesis. These kinds of strategies can be a powerful approach for identifying novel pathways or proteins involved in the regulatory network of mitochondrial function.
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By combining the results of several phenotypic tests, it is possible to define a comprehensive set of mitochondrial signatures that enable the clustering of novel chemical entities according to their footprint on mitochondrial function. Such a signature will also help determine the particular mitochondrial signalling pathway that is affected, facilitating downstream target deconvolution.
Abstract
Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders but also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson's disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models as well as multicellular organisms have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for several diseases, which has spurred active drug discovery efforts in this area.
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References
Wallin, I. E. Symbionticism and the Origin of Species (Williams & Wilkins Company, 1927).
Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008). This study provides the list of mitochondrial proteins.
Ryan, M. T. & Hoogenraad, N. J. Mitochondrial-nuclear communications. Annu. Rev. Biochem. 76, 701–722 (2007).
Haynes, C. M. & Ron, D. The mitochondrial UPR — protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).
Schmidt, O., Pfanner, N. & Meisinger, C. Mitochondrial protein import: from proteomics to functional mechanisms. Nature Rev. Mol. Cell Biol. 11, 655–667 (2010).
Rugarli, E. I. & Langer, T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 31, 1336–1349 (2012).
Westermann, B. Mitochondrial fusion and fission in cell life and death. Nature Rev. Mol. Cell Biol. 11, 872–884 (2010).
Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature Rev. Mol. Cell Biol. 12, 9–14 (2011).
Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).
Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).
Patti, M. E. & Corvera, S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr. Rev. 31, 364–395 (2010).
Vafai, S. B. & Mootha, V. K. Mitochondrial disorders as windows into an ancient organelle. Nature 491, 374–383 (2012).
Wallace, D. C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).
Shoubridge, E. A. Cytochrome c oxidase deficiency. Am. J. Med. Genet. 106, 46–52 (2001).
Kerstann, K., Brown, M., Vockley, I. & Wallace, D. in The Metabolic and Molecular Bases of Inherited Disease 8th Edn Ch. 105 (eds Valle, P. et al.) (McGraw-Hill, 2001).
Sharpley, M. S. et al. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition. Cell 151, 333–343 (2012). This paper demonstrates that heteroplasmy for two wild-type mtDNAs is sufficient to alter metabolism and cognitive function in mice.
Jenuth, J. P., Peterson, A. C. & Shoubridge, E. A. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nature Genet 16, 93–95 (1997). This study reports that mtDNA segregates differently from one tissue to another.
Zeviani, M. & Di Donato, S. Mitochondrial disorders. Brain 127, 2153–2172 (2004).
Koene, S. & Smeitink, J. Mitochondrial medicine: entering the era of treatment. J. Intern. Med. 265, 193–209 (2009).
Wallace, D. C., Fan, W. & Procaccio, V. Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5, 297–348 (2010).
Andreux, P. A. et al. Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. Cell 150, 1287–1299 (2012). This paper exploits the BXD strains as a potential resource for the complex genetics underlying metabolic phenotypes related to mitochondrial dysfunction.
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Rev. Mol. Cell Biol. 13, 251–262 (2012).
Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell Biol. 13, 225–238 (2012).
Houtkooper, R. H., Williams, R. W. & Auwerx, J. Metabolic networks of longevity. Cell 142, 9–14 (2010).
Corsetti, G. et al. Morphometric changes induced by amino acid supplementation in skeletal and cardiac muscles of old mice. Am J. Cardiol 101, 26e–34e (2008).
Boudina, S. et al. Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 119, 1272–1283 (2009).
Hyyti, O. M., Ledee, D., Ning, X. H., Ge, M. & Portman, M. A. Aging impairs myocardial fatty acid and ketone oxidation and modifies cardiac functional and metabolic responses to insulin in mice. Am. J. Physiol. Heart Circ. Physiol. 299, H868–H875 (2010).
Houtkooper, R. H. et al. The metabolic footprint of aging in mice. Sci. Rep. 1, 134 (2011).
Sinha, R. et al. Assessment of skeletal muscle triglyceride content by 1H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes 51, 1022–1027 (2002).
Kotronen, A., Seppala-Lindroos, A., Bergholm, R. & Yki-Jarvinen, H. Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome. Diabetologia 51, 130–138 (2008).
Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R. & Shulman, G. I. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664–671 (2004).
Hwang, H. et al. Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes 59, 33–42 (2010).
Mootha, V. K. et al. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 115, 629–640 (2003).
Patti, M. E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc. Natl Acad. Sci. USA 100, 8466–8471 (2003).
Krishnan, J. et al. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev. 26, 259–270 (2012).
Mustelin, L. et al. Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity. Am. J. Physiol. Endocrinol. Metab. 295, e148–e154 (2008).
Pihlajamaki, J. et al. Thyroid hormone-related regulation of gene expression in human fatty liver. J. Clin. Endocrinol. Metab. 94, 3521–3529 (2009).
Takamura, T. et al. Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity 16, 2601–2609 (2008).
Poussin, C. et al. Oxidative phosphorylation flexibility in the liver of mice resistant to high-fat diet-induced hepatic steatosis. Diabetes 60, 2216–2224 (2011).
Auwerx, J. Improving metabolism by increasing energy expenditure. Nature Med. 12, 44–45 (2006).
Meex, R. C. et al. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes 59, 572–579 (2010).
Phielix, E., Meex, R., Moonen-Kornips, E., Hesselink, M. K. & Schrauwen, P. Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia 53, 1714–1721 (2010).
Pospisilik, J. A. et al. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131, 476–491 (2007).
Vernochet, C. et al. Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab. 16, 765–776 (2012).
Douglas, P. M. & Dillin, A. Protein homeostasis and aging in neurodegeneration. J. Cell Biol. 190, 719–729 (2010).
Valente, E. M. et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am. J. Hum. Genet. 68, 895–900 (2001).
Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
Dagda, R. K. et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843–13855 (2009).
Cui, M., Tang, X., Christian, W. V., Yoon, Y. & Tieu, K. Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. J. Biol. Chem. 285, 11740–11752 (2010).
Kamp, F. et al. Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J. 29, 3571–3589 (2010).
Krebiehl, G. et al. Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1. PLoS ONE 5, e9367 (2010).
Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).
Hansson Petersen, C. A. et al. The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl Acad. Sci. USA 105, 13145–13150 (2008).
Barsoum, M. J. et al. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J. 25, 3900–3911 (2006).
Aleardi, A. M. et al. Gradual alteration of mitochondrial structure and function by β-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release. J. Bioenerg. Biomembr. 37, 207–225 (2005).
Crouch, P. J. et al. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1–42. J. Neurosci. 25, 672–679 (2005).
Area-Gomez, E. et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 31, 4106–4123 (2012).
Coskun, P. et al. A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim. Biophys. Acta 1820, 553–564 (2012).
Fukui, H., Diaz, F., Garcia, S. & Moraes, C. T. Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 104, 14163–14168 (2007).
Fulda, S., Galluzzi, L. & Kroemer, G. Targeting mitochondria for cancer therapy. Nature Rev. Drug Discov. 9, 447–464 (2010).
Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).
Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span — from yeast to humans. Science 328, 321–326 (2010).
Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).
Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012). References 66 and 67 show divergent results of the impact of caloric restriction on health and lifespan in non-human primates.
Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–780 (2000).
Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006).
Yamamoto, H. et al. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147, 827–839 (2011).
Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).
Motta, M. C. et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551–563 (2004).
van der Horst, A. et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J. Biol. Chem. 279, 28873–28879 (2004).
Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).
Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
Beher, D. et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem. Biol. Drug Des. 74, 619–624 (2009).
Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009). This study defines the importance of the AMPK–SIRT1–PGC1α signaling axis in mitochondrial function.
Canto, C. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11, 213–219 (2010).
Pacholec, M. et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285, 8340–8351 (2010).
Um, J. H. et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59, 554–563 (2010).
Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).
Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006). References 81 and 82 provide the first evidence of a beneficial impact of resveratrol on mitochondrial function and healthspan in mice.
Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612–622 (2011).
Brasnyo, P. et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br. J. Nutr. 106, 383–389 (2011).
Poulsen, M. M. et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 62, 1186–1195 (2012).
Yoshino, J. et al. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 16, 658–664 (2012).
Bhatt, J. K., Thomas, S. & Nanjan, M. J. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 32, 537–541 (2012).
Patel, K. R. et al. Clinical trials of resveratrol. Ann. NY Acad. Sci. 1215, 161–169 (2011).
Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007).
Feige, J. N. et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 8, 347–358 (2008).
Dai, H. et al. SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. J. Biol. Chem. 285, 32695–32703 (2010).
Baur, J. A., Ungvari, Z., Minor, R. K., Le Couteur, D. G. & de Cabo, R. Are sirtuins viable targets for improving healthspan and lifespan? Nature Rev. Drug Discov. 11, 443–461 (2012).
Hubbard, B. P. et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339, 1216–1219 (2013).
Minor, R. K. et al. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 1, 70 (2011).
Qi, Y. et al. SRT2104, a novel small molecule SIRT1 activator ameliorates insulin resistance and promotes glucose utilization measured under a hyperinsulinemic-euglycemic clamp by enhancing both glycolysis and carbohydrate oxidation in mice fed a high fat diet. Diabetes 60 (Suppl. 1), Abstract 1007-P (2011).
Suri, V. et al. The metabolomic profile of SRT2104, a selective SIRT1 activator in high fat diet fed mice reveals significant improvements in metabolic function in liver, heart and skeletal muscle. Diabetes 60 (Suppl. 1), Abstract 1706-P (2011).
Hoffmann, E. et al. Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man. Br. J. Clin. Pharmacol. 75, 186–196 (2013).
Bemis, J. E. et al. Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators. Bioorg. Med. Chem. Lett. 19, 2350–2353 (2009).
Mai, A. et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J. Med. Chem. 52, 5496–5504 (2009).
Vu, C. B. et al. Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators. J. Med. Chem. 52, 1275–1283 (2009).
Houtkooper, R. H., Canto, C., Wanders, R. J. & Auwerx, J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr. Rev. 31, 194–223 (2010).
Houtkooper, R. H. & Auwerx, J. Exploring the therapeutic space around NAD+. J. Cell Biol. 199, 205–209 (2012).
Canto, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012).
Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).
Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011).
Barbosa, M. T. et al. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J. 21, 3629–3639 (2007). References 103–106 (four independent studies) define the importance of NAD+ levels and SIRT activation in mitochondrial homeostasis.
Canto, C. & Auwerx, J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407–3423 (2010).
Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).
Viscomi, C. et al. In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. Cell Metab. 14, 80–90 (2011). This paper shows that the AMPK agonist AICAR is beneficial for this form of inherited mitochondrial disease in mice.
Zoncu, R. Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This key report demonstrates the beneficial impact of the mTOR inhibitor rapamycin on mouse lifespan.
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
Robida-Stubbs, S. et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012).
Polak, P. et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8, 399–410 (2008).
Bentzinger, C. F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008).
Schoonjans, K., Staels, B. & Auwerx, J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J. Lipid Res. 37, 907–925 (1996).
Evans, R. M., Barish, G. D. & Wang, Y. X. PPARs and the complex journey to obesity. Nature Med. 10, 355–361 (2004).
Michalik, L. et al. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev. 58, 726–741 (2006).
Kersten, S. et al. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489–1498 (1999).
Leibowitz, M. D. et al. Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Lett. 473, 333–336 (2000).
Tanaka, T. et al. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl Acad. Sci. USA 100, 15924–15929 (2003).
Riserus, U. et al. Activation of peroxisome proliferator-activated receptor (PPAR)δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 57, 332–339 (2008).
Djouadi, F. et al. Bezafibrate increases very-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders. Hum. Mol. Genet. 14, 2695–2703 (2005).
Gobin-Limballe, S. et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am. J. Hum. Genet. 81, 1133–1143 (2007).
Bonnefont, J. P. et al. Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency. Clin. Pharmacol. Ther. 88, 101–108 (2010). This study shows that PPARδ activation with bezafibrate has beneficial therapeutic effects in patients with fatty acid oxidation deficiency.
Heikkinen, S., Auwerx, J. & Argmann, C. A. PPARγ in human and mouse physiology. Biochim. Biophys. Acta 1771, 999–1013 (2007).
Kung, J. & Henry, R. R. Thiazolidinedione safety. Expert Opin. Drug Saf. 11, 565–579 (2012).
Rocchi, S. et al. A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol. Cell 8, 737–747 (2001).
Choi, J. H. et al. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature 477, 477–481 (2011).
Knouff, C. & Auwerx, J. Peroxisome proliferator-activated receptor-γ calls for activation in moderation: lessons from genetics and pharmacology. Endocr. Rev. 25, 899–918 (2004).
Chae, S. et al. A systems approach for decoding mitochondrial retrograde signaling pathways. Sci. Signal. 6, rs4 (2013).
Giguere, V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr. Rev. 29, 677–696 (2008).
Dufour, C. R. et al. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRα and γ. Cell Metab. 5, 345–356 (2007).
Schreiber, S. N. et al. The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis. Proc. Natl Acad. Sci. USA 101, 6472–6477 (2004).
Alaynick, W. A. et al. ERRγ directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab. 6, 13–24 (2007).
Coward, P., Lee, D., Hull, M. V. & Lehmann, J. M. 4-hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ. Proc. Natl Acad. Sci. USA 98, 8880–8884 (2001).
Zuercher, W. J. et al. Identification and structure–activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRβ and ERRγ. J. Med. Chem. 48, 3107–3109 (2005).
Kim, Y., Koh, M., Kim, D. K., Choi, H. S. & Park, S. B. Efficient discovery of selective small molecule agonists of estrogen-related receptor γ using combinatorial approach. J. Comb. Chem. 11, 928–937 (2009).
Willy, P. J. et al. Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand. Proc. Natl Acad. Sci. USA 101, 8912–8917 (2004).
Chisamore, M. J., Cunningham, M. E., Flores, O., Wilkinson, H. A. & Chen, J. D. Characterization of a novel small molecule subtype specific estrogen-related receptor α antagonist in MCF-7 breast cancer cells. PLoS ONE 4, e5624 (2009).
Patch, R. J. et al. Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents. J. Med. Chem. 54, 788–808 (2011).
Kallen, J. et al. Crystal structure of human estrogen-related receptor α in complex with a synthetic inverse agonist reveals its novel molecular mechanism. J. Biol. Chem. 282, 23231–23239 (2007).
Hyatt, S. M. et al. On the intractability of estrogen-related receptor α as a target for activation by small molecules. J. Med. Chem. 50, 6722–6724 (2007).
Kim, D. K. et al. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is key regulator of hepatic gluconeogenesis. J. Biol. Chem. 287, 21628–21639 (2012).
Kelly, D. P. & Scarpulla, R. C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18, 357–368 (2004).
Collard, J. & Khorkova Sherman, O. Treatment of nuclear respiratory factor 1 (NRF1) related diseases by inhibition of natural antisense transcript to NRF1. US Patent 20120264812 A1 (2010).
Iyer, S. et al. Recombinant mitochondrial transcription factor A with N-terminal mitochondrial transduction domain increases respiration and mitochondrial gene expression. Mitochondrion 9, 196–203 (2009).
Thomas, R. R. et al. RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice. Aging 4, 620–635 (2012).
Iyer, S. et al. Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells. Hum. Gene Ther. 23, 647–657 (2012).
Ylikallio, E., Tyynismaa, H., Tsutsui, H., Ide, T. & Suomalainen, A. High mitochondrial DNA copy number has detrimental effects in mice. Hum. Mol. Genet. 19, 2695–2705 (2010).
Picard, F. et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111, 931–941 (2002).
Coste, A. et al. The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α. Proc. Natl Acad. Sci. USA 105, 17187–17192 (2008).
Coste, A. et al. Absence of the steroid receptor coactivator-3 induces B-cell lymphoma. EMBO J. 25, 2453–2464 (2006).
Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451–456 (2010).
Ye, L. et al. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 151, 96–110 (2012).
Bostrom, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).
Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006).
Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010).
Li, P. et al. Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell 147, 815–826 (2011).
Iezzi, S. et al. Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin. Dev. Cell 6, 673–684 (2004).
Fajas, L. et al. The retinoblastoma–histone deacetylase 3 complex inhibits PPARγ and adipocyte differentiation. Dev. Cell 3, 903–910 (2002).
Sun, Z. et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nature Med. 18, 934–942 (2012).
Debevec, D. et al. Receptor interacting protein 140 regulates expression of uncoupling protein 1 in adipocytes through specific peroxisome proliferator activated receptor isoforms and estrogen-related receptor α. Mol. Endocrinol. 21, 1581–1592 (2007).
Seth, A. et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab. 6, 236–245 (2007).
Leonardsson, G. et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc. Natl Acad. Sci. USA 101, 8437–8442 (2004).
Powelka, A. M. et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J. Clin. Invest. 116, 125–136 (2006).
Blanchet, E. et al. E2F transcription factor-1 regulates oxidative metabolism. Nature Cell Biol. 13, 1146–1152 (2011).
Scime, A. et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1α. Cell Metab. 2, 283–295 (2005).
Dali-Youcef, N. et al. Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure. Proc. Natl Acad. Sci. USA 104, 10703–10708 (2007).
Calo, E. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010).
White, R. et al. The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility. Nature Med. 6, 1368–1374 (2000).
Brand, M. D. The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 45, 466–472 (2010).
Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158–167 (2012).
Brand, M. D. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp. Gerontol. 35, 811–820 (2000).
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).
Chan, D. C. Mitochondria: dynamic organelles in disease, aging, and development. Cell 125, 1241–1252 (2006).
Alexander, C. et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genet. 26, 211–215 (2000).
Zuchner, S. et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot–Marie–Tooth neuropathy type 2A. Nature Genet. 36, 449–451 (2004).
Waterham, H. R. et al. A lethal defect of mitochondrial and peroxisomal fission. N. Engl. J. Med. 356, 1736–1741 (2007).
Ishihara, N. et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nature Cell Biol. 11, 958–966 (2009).
Chen, H., Chomyn, A. & Chan, D. C. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280, 26185–26192 (2005).
Parone, P. A. et al. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3, e3257 (2008).
Soriano, F. X. et al. Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-γ coactivator-1α, estrogen-related receptor-α, and mitofusin 2. Diabetes 55, 1783–1791 (2006).
Cartoni, R. et al. Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exercise. J. Physiol. 567, 349–358 (2005).
Wang, D. et al. A small molecule promotes mitochondrial fusion in mammalian cells. Angew. Chem. Int. Ed Engl. 51, 9302–9305 (2012). This paper reports the identification of a small molecule that stimulates mitochondrial fusion in mammalian cells.
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). This study identifies a small molecule that inhibits mitochondrial fission in yeast.
Lackner, L. L. & Nunnari, J. Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine. Chem. Biol. 17, 578–583 (2010).
Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nature Rev. Mol. Cell Biol. 10, 458–467 (2009).
Yang, Z. & Klionsky, D. J. Eaten alive: a history of macroautophagy. Nature Cell Biol. 12, 814–822 (2010).
Sandoval, H. et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454, 232–235 (2008).
Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010). This key paper demonstrates the recruitment of PINK1 as a stimulator of mitophagy.
Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biol. 12, 119–131 (2010).
Lee, J. Y., Nagano, Y., Taylor, J. P., Lim, K. L. & Yao, T. P. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J. Cell Biol. 189, 671–679 (2010).
Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211–221 (2010).
Sterky, F. H., Lee, S., Wibom, R., Olson, L. & Larsson, N. G. Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc. Natl Acad. Sci. USA 108, 12937–12942 (2011).
Gegg, M. E. et al. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 19, 4861–4870 (2010).
Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367–1380 (2010).
Hartl, F. U., Bracher, A. & Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011).
Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. & Haynes, C. M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012). This report describes another layer of transcriptional control of the mitochondrial UPR by regulating the subcellular distribution of ATFS-1.
Benedetti, C., Haynes, C. M., Yang, Y., Harding, H. P. & Ron, D. Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response. Genetics 174, 229–239 (2006).
Durieux, J., Wolff, S. & Dillin, A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79–91 (2011). This study demonstrates that lifespan extension in C. elegans following mitochondrial dysfunction in the neurons requires the mitochondrial UPR in distal tissues. It also defines the concept of a mitokine.
Tyynismaa, H. et al. Mitochondrial myopathy induces a starvation-like response. Hum. Mol. Genet. 19, 3948–3958 (2010).
Suomalainen, A. et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 10, 806–818 (2011).
Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nature Med. 19, 83–92 (2012). References 203 and 204 suggest that FGF21 can function as a mitokine.
Lee, C., Yen, K. & Cohen, P. Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol. Metab. 8 Feb 2013 (10.1016/j.tem.2013.01.005).
Martinus, R. D. et al. Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur. J. Biochem. 240, 98–103 (1996).
Houtkooper, R. H. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature (in the press). This recently published paper shows that the imbalance between mitochondrial and nuclear proteins triggers the mitochondrial UPR, which is an overarching mechanism that enhances lifespan.
Fontaine, B. et al. A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am. J. Hum. Genet. 66, 702–707 (2000).
Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).
Nolden, M. et al. The m-AAA protease defective in hereditary spastic paraplegia controls ribosome assembly in mitochondria. Cell 123, 277–289 (2005).
Ventura, N. et al. p53/CEP-1 increases or decreases lifespan, depending on level of mitochondrial bioenergetic stress. Aging Cell 8, 380–393 (2009).
Guillon, B. et al. Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins. FEBS J. 276, 1036–1047 (2009).
Rotig, A. et al. Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia. Nature Genet. 17, 215–217 (1997).
Bieganowski, P. & Brenner, C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 117, 495–502 (2004).
Sato, H. et al. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun. 362, 793–798 (2007).
Sato, H. et al. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure–activity relationships, and molecular modeling studies. J. Med. Chem. 51, 1831–1841 (2008).
Evans, K. A. et al. Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists. J. Med. Chem. 52, 7962–7965 (2009).
Pellicciari, R. et al. Discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J. Med. Chem. 52, 7958–7961 (2009).
Genet, C. et al. Structure–activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes. J. Med. Chem. 53, 178–190 (2010).
Herbert, M. R. et al. Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5. Bioorg. Med. Chem. Lett. 20, 5718–5721 (2010).
Londregan, A. T. et al. Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries. Bioorg. Med. Chem. Lett. 23, 1407–1411 (2013).
Moreno, D., Knecht, E., Viollet, B. & Sanz, P. A769662, a novel activator of AMP-activated protein kinase, inhibits non-proteolytic components of the 26S proteasome by an AMPK-independent mechanism. FEBS Lett. 582, 2650–2654 (2008).
Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).
Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85–95 (2011).
Kitami, T. et al. A chemical screen probing the relationship between mitochondrial content and cell size. PLoS ONE 7, e33755 (2012). This study reports the set-up of an image-based phenotypic screen for the identification of compounds that increase mitochondrial content per cell using a primary cell line.
Beeson, C. C., Beeson, G. C. & Schnellmann, R. G. A high-throughput respirometric assay for mitochondrial biogenesis and toxicity. Anal. Biochem. 404, 75–81 (2010).
Kikkawa, R., Yamamoto, T., Fukushima, T., Yamada, H. & Horii, I. Investigation of a hepatotoxicity screening system in primary cell cultures — “what biomarkers would need to be addressed to estimate toxicity in conventional and new approaches?”. J. Toxicol. Sci. 30, 61–72 (2005).
Li, A. P. Screening for human ADME/Tox drug properties in drug discovery. Drug Discov. Today 6, 357–366 (2001).
Couplan, E. et al. A yeast-based assay identifies drugs active against human mitochondrial disorders. Proc. Natl Acad. Sci. USA 108, 11989–11994 (2011).
Burns, A. R. et al. High-throughput screening of small molecules for bioactivity and target identification in Caenorhabditis elegans. Nature Protoc. 1, 1906–1914 (2006). References 229 and 230 are examples of phenotypic screens for mitochondrial function performed in C. elegans and yeast.
Segalat, L. Invertebrate animal models of diseases as screening tools in drug discovery. ACS Chem. Biol. 2, 231–236 (2007).
Gohil, V. M. et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nature Biotech. 28, 249–255 (2010).
Wagner, B. K. et al. Large-scale chemical dissection of mitochondrial function. Nature Biotech. 26, 343–351 (2008). References 232 and 233 describe two examplary phenotypic screens for mitochondrial function in mammalian cells.
Tsang, W. Y. & Lemire, B. D. Mitochondrial genome content is regulated during nematode development. Biochem. Biophys. Res. Commun. 291, 8–16 (2002).
Detmer, S. A. & Chan, D. C. Functions and dysfunctions of mitochondrial dynamics. Nature Rev. Mol. Cell Biol. 8, 870–879 (2007).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
Frayling, T. M. Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nature Rev. Genet. 8, 657–662 (2007).
Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature Genet. 40, 638–645 (2008).
Mair, W. & Dillin, A. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727–754 (2008).
Handschin, C. & Spiegelman, B. M. Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr. Rev. 27, 728–735 (2006).
Fernandez-Marcos, P. J. & Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J. Clin. Nutr. 93, 884S–890S (2011).
Canto, C. & Auwerx, J. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20, 98–105 (2009).
Jeninga, E. H., Schoonjans, K. & Auwerx, J. Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29, 4617–4624 (2010).
Feige, J. N., Gelman, L., Michalik, L., Desvergne, B. & Wahli, W. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog. Lipid Res. 45, 120–159 (2006).
Feige, J. N. & Auwerx, J. Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol. 17, 292–301 (2007).
Scarpulla, R. C., Vega, R. B. & Kelly, D. P. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459–466 (2012).
Kalyanaraman, B. et al. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic. Biol. Med. 52, 1–6 (2012).
Meyer, A. J. & Dick, T. P. Fluorescent protein-based redox probes. Antioxid. Redox Signal. 13, 621–650 (2010).
Greer, E. L. et al. An AMPK–FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr. Biol. 17, 1646–1656 (2007).
Acknowledgements
The authors thank R. Wanders for critically reading the manuscript. R.H.H. is financially supported by an AMC Postdoctoral fellowship and a ZonMw-VENI grant (number 91613050). J.A. is the Nestlé Chair in Energy Metabolism and work in his laboratory is supported by the École polytechnique fédérale de Lausanne (EPFL), the EU Ideas program (ERC-2008-AdG-231138), the US National Institutes of Health (grants 1R01HL 106511-01A1 and R01AG043930), the Velux Stiftung Research Grant Program and the Swiss National Science Foundation (grants 31003A-124713 and CRSII3-136201).
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Glossary
- Mitochondrial DNA
-
(mtDNA). A 16.5 kb circular DNA sequence carried within mitochondria, composed of a light and heavy strand. Both strands contain 37 genes, including 13 that encode protein subunits of the oxidative phosphorylation complexes, whereas the remaining encode ribosomal RNA and tRNA molecules that are essential for the transcription and synthesis of mitochondrially encoded proteins.
- Oxidative phosphorylation
-
Enzymatic phosphorylation of ADP to ATP, which is coupled to electron transfer from a substrate to molecular oxygen in the electron transport chain.
- Heteroplasmy
-
A mixture of different forms of mitochondrial DNA within a single cell.
- Quantitative trait loci
-
(QTLs). Genetic loci contributing quantitatively to a trait or phenotype. A QTL partly explains the genetic contribution to a given phenotype.
- Proteostasis
-
Homeostasis of the protein folding landscape.
- mtDNA haplogroup
-
A group sharing the same single nucleotide polymorphism on mitochondrial DNA (mtDNA). Some haplogroups have been suggested to have a greater likelihood of predisposing individuals to Alzheimer's disease.
- Caloric restriction diet
-
A diet that involves the consumption of 20–50% less calories than normal without causing malnutrition: that is, with maintenance of proper vitamin and mineral intake.
- NAD+
-
The oxidized version of NAD; serves as a co-factor in oxidation–reduction reactions. NAD+ also acts as an obligatory co-substrate for sirtuin-mediated deacylation reactions.
- Inverse agonists
-
Compounds that bind to the same receptor binding site as a prototypical agonist for that given receptor. Through this binding, inverse agonists reverse the basal or constitutive activity of the receptor. Oestrogen-related receptor-α is an example of a constitutively active nuclear receptor for which inverse agonists exist.
- Myokine
-
A signalling molecule that is produced by the muscle and has cytokine-like properties.
- Mitokine
-
A signalling molecule that is produced by mitochondria in a given tissue and affects mitochondrial function in a distinct tissue.
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Andreux, P., Houtkooper, R. & Auwerx, J. Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov 12, 465–483 (2013). https://doi.org/10.1038/nrd4023
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DOI: https://doi.org/10.1038/nrd4023
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