Repairing Mitochondrial Dysfunction in Disease

Literature Cited

1. Youle RJ, Narendra DP. 1.  2011. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12:9–14 [Google Scholar]
2. Archer SL. 2.  2013. Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N. Engl. J. Med. 369:2236–51 [Google Scholar]
3. Jovaisaite V, Auwerx J. 3.  2015. The mitochondrial unfolded protein response—synchronizing genomes. Curr. Opin. Cell Biol. 33:74–81 [Google Scholar]
4. Wang X, Chen XJ. 4.  2015. A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524:481–84 [Google Scholar]
5. Nunnari J, Suomalainen A. 5.  2012. Mitochondria: in sickness and in health. Cell 148:1145–59 [Google Scholar]
6. Vafai SB, Mootha VK. 6.  2012. Mitochondrial disorders as windows into an ancient organelle. Nature 491:374–83 [Google Scholar]
7. Luft R. 7.  1994. The development of mitochondrial medicine. PNAS 91:8731–38 [Google Scholar]
8. Dimauro S. 8.  2004. Mitochondrial medicine. Biochim. Biophys. Acta 1659:107–14 [Google Scholar]
9. Wallace DC. 9.  2005. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39:359–407 [Google Scholar]
10. Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI. 10.  et al. 2009. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–45 [Google Scholar]
11. Houtkooper RH, Pirinen E, Auwerx J. 11.  2012. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13:225–38 [Google Scholar]
12. Bhatti JS, Bhatti GK, Reddy PH. 12.  2017. Mitochondrial dysfunction and oxidative stress in metabolic disorders—a step towards mitochondria based therapeutic strategies. Biochim. Biophys. Acta 1863:1066–77 [Google Scholar]
13. Seillier M, Pouyet L, N'Guessan P, Nollet M, Capo F. 13.  et al. 2015. Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1. EMBO Mol. Med. 7:802–18 [Google Scholar]
14. Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M. 14.  et al. 2007. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131:476–91 [Google Scholar]
15. Loh K, Deng H, Fukushima A, Cai X, Boivin B. 15.  et al. 2009. Reactive oxygen species enhance insulin sensitivity. Cell Metab 10:260–72 [Google Scholar]
16. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM. 16.  et al. 2013. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19:83–92 [Google Scholar]
17. Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL. 17.  et al. 2016. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat. Rev. Cardiol. 14:238–50 [Google Scholar]
18. Halestrap AP, Pasdois P. 18.  2009. The role of the mitochondrial permeability transition pore in heart disease. Biochim. Biophys. Acta 1787:1402–15 [Google Scholar]
19. Boudina S, Sena S, O'Neill BT, Tathireddy P, Young ME, Abel ED. 19.  2005. Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 112:2686–95 [Google Scholar]
20. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD. 20.  et al. 2004. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109:2191–96 [Google Scholar]
21. Dogan SA, Pujol C, Maiti P, Kukat A, Wang S. 21.  et al. 2014. Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart. Cell Metab 19:458–69 [Google Scholar]
22. Chen Y, Liu Y, Dorn GW II. 22.  2011. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ. Res. 109:1327–31 [Google Scholar]
23. Dorn GW II, Clark CF, Eschenbacher WH, Kang MY, Engelhard JT. 23.  et al. 2011. MARF and Opa1 control mitochondrial and cardiac function in Drosophila. Circ. Res. 108:12–17 [Google Scholar]
24. Wai T, García-Prieto J, Baker MJ, Merkwirth C, Benit P. 24.  et al. 2015. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116 [Google Scholar]
25. Pennanen C, Parra V, López-Crisosto C, Morales PE, Del Campo A. 25.  et al. 2014. Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca²⁺-calcineurin signaling pathway. J. Cell Sci. 127:2659–71 [Google Scholar]
26. Montaigne D, Marechal X, Coisne A, Debry N, Modine T. 26.  et al. 2014. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 130:554–64 [Google Scholar]
27. Bugger H, Chen D, Riehle C, Soto J, Theobald HA. 27.  et al. 2009. Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic Akita mice. Diabetes 58:1986–97 [Google Scholar]
28. Winnik S, Auwerx J, Sinclair DA, Matter CM. 28.  2015. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur. Heart J. 36:3404–12 [Google Scholar]
29. Luo Y-X, Tang X, An XZ, Xie XM, Chen XF. 29.  et al. 2016. Sirt4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity. Eur. Heart J. 38:1389–98 [Google Scholar]
30. Martin OJ, Lai L, Soundarapandian MM, Leone TC, Zorzano A. 30.  et al. 2014. A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth. Circ. Res. 114:626–36 [Google Scholar]
31. Sebastiani M, Giordano C, Nediani C, Travaglini C, Borchi E. 31.  et al. 2007. Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies. J. Am. Coll. Cardiol. 50:1362–69 [Google Scholar]
32. Rontoyanni VG, Lopez ON, Fankhauser GT, Cheema ZF, Rasmussen BB, Porter C. 32.  2017. Mitochondrial bioenergetics in the metabolic myopathy accompanying peripheral artery disease. Front. Physiol. 8:141 [Google Scholar]
33. Xie A, Gao J, Xu L, Meng D. 33.  2014. Shared mechanisms of neurodegeneration in Alzheimer's disease and Parkinson's disease. BioMed. Res. Int. 2014:648740 [Google Scholar]
34. Lin MT, Beal MF. 34.  2006. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–95 [Google Scholar]
35. Buchpiguel CA. 35.  et al. 1991. Radioisotopic assessment of peripheral and cardiac muscle involvement and dysfunction in polymyositis/dermatomyositis. J. Rheumatol. 18:1359–63 [Google Scholar]
36. Selfridge JE, Lezi E, Lu J, Swerdlow RH. 36.  2013. Role of mitochondrial homeostasis and dynamics in Alzheimer's disease. Neurobiol. Dis. 51:3–12 [Google Scholar]
37. Stewart VC, Sharpe MA, Clark JB, Heales SJR. 37.  2000. Astrocyte-derived nitric oxide causes both reversible and irreversible damage to the neuronal mitochondrial respiratory chain. J. Neurochem. 75:694–700 [Google Scholar]
38. Zhou M, Ottenberg G, Sferrazza GF, Hubbs C, Fallahi M. 38.  et al. 2015. Neuronal death induced by misfolded prion protein is due to NAD⁺ depletion and can be relieved in vitro and in vivo by NAD⁺ replenishment. Brain 138:992 [Google Scholar]
39. Mena NP, Urrutia PJ, Lourido F, Carrasco CM, Nuñez MT. 39.  2015. Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders. Mitochondrion 21:92–105 [Google Scholar]
40. Horowitz MP, Greenamyre JT. 40.  2010. Mitochondrial iron metabolism and its role in neurodegeneration. J. Alzheimer's Dis. 20:S551–68 [Google Scholar]
41. Bratic A, Larsson NG. 41.  2013. The role of mitochondria in aging. J. Clin. Investig. 123:951–57 [Google Scholar]
42. Lee YK, Lau YM, Ng KM, Lai WH, Ho SL. 42.  et al. 2016. Corrigendum to ‘Efficient attenuation of Friedreich's ataxia (FRDA) cardiomyopathy by modulation of iron homeostasis-human induced pluripotent stem cell (hiPSC) as a drug screening platform for FRDA’ [Int J Cardiol 203 (2016) 964–971]. Int. J. Cardiol. 207:393 [Google Scholar]
43. Cenini G, Rüb C, Bruderek M, Voos W. 43.  2016. Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process. Mol. Biol. Cell 27:3257–72 [Google Scholar]
44. Mossmann D, Vögtle FN, Taskin AA, Teixeira PF, Ring J. 44.  et al. 2014. Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab 20:662–69 [Google Scholar]
45. Vento S, Di Perri G, Garofano T, Concia E, Bassetti D. 45.  1989. Reactivation of hepatitis B in AIDS. Lancet 334:108–9 [Google Scholar]
46. Beck JS, Mufson EJ, Counts SE. 46.  2016. Evidence for mitochondrial UPR gene activation in familial and sporadic Alzheimer's disease. Curr. Alzheimer Res. 13:610–14 [Google Scholar]
47. Lee HR, Shin HK, Park SY, Kim HY, Lee WS. 47.  et al. 2014. Cilostazol suppresses β-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-β. J. Neurosci. Res. 92:1581–90 [Google Scholar]
48. Abbas N, Lücking CB, Ricard S, Dürr A, Bonifati V. 48.  et al. 1999. A wide variety of mutations in the Parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum. Mol. Genet. 8:567–74 [Google Scholar]
49. Dawson TM, Dawson VL. 49.  2010. The role of parkin in familial and sporadic Parkinson's disease. Mov. Disord. 25:Suppl. 1S32–39 [Google Scholar]
50. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y. 50.  et al. 1998. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608 [Google Scholar]
51. Jin SM, Youle RJ. 51.  2012. PINK1- and Parkin-mediated mitophagy at a glance. J. Cell Sci. 125:795–799 [Google Scholar]
52. Kamp F, Exner N, Lutz AK, Wender N, Hegermann J. 52.  et al. 2010. Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J 29:3571–89 [Google Scholar]
53. Nakamura N, Hirose S. 53.  2008. Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol. Biol. Cell 19:1903–11 [Google Scholar]
54. Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE. 54.  et al. 2014. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510:370–75 [Google Scholar]
55. Lehmann S, Loh SHY, Martins LM. 55.  2017. Enhancing NAD⁺ salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease. Biol. Open 6:141–47 [Google Scholar]
56. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J. 56.  et al. 2006. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408 [Google Scholar]
57. Zheng L, Bernard-Marissal N, Moullan N, D'Amico D, Auwerx J. 57.  et al. 2017. Parkin functionally interacts with PGC-1α to preserve mitochondria and protect dopaminergic neurons. Hum. Mol. Genet. 26:582–98 [Google Scholar]
58. Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. 58.  2007. A lethal defect of mitochondrial and peroxisomal fission. N. Engl. J. Med. 356:1736–41 [Google Scholar]
59. Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO. 59.  et al. 2009. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat. Cell Biol. 11:958–66 [Google Scholar]
60. Alexander C, Votruba M, Pesch UEA, Thiselton DL, Mayer S. 60.  et al. 2000. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat. Genet. 26:211–15 [Google Scholar]
61. Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J. 61.  et al. 2004. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 36:449–51 [Google Scholar]
62. Hoffman EP, Brown RH Jr., Kunkel LM. 62.  1987. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919–28 [Google Scholar]
63. Sperl W, Skladal D, Gnaiger E, Wyss M, Mayr U. 63.  et al. 1997. High resolution respirometry of permeabilized skeletal muscle fibers in the diagnosis of neuromuscular disorders. Mol. Cell. Biochem. 174:71–78 [Google Scholar]
64. Ryu D, Zhang H, Ropelle ER, Sorrentino V, Mázala DAG. 64.  et al. 2016. NAD⁺ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci. Transl. Med. 8:361ra139 [Google Scholar]
65. Ljubicic V, Miura P, Burt M, Boudreault L, Khogali S. 65.  et al. 2011. Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle. Hum. Mol. Genet. 20:3478–93 [Google Scholar]
66. Pauly M, Daussin F, Burelle Y, Li T, Godin R, Fauconnier J. 66.  et al. 2012. AMPK activation stimulates autophagy and ameliorates muscular dystrophy in the mdx mouse diaphragm. Am. J. Pathol. 181:583–92 [Google Scholar]
67. Zhang H, Ryu D, Wu Y, Gariani K, Wang X. 67.  et al. 2016. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352:1436–43 [Google Scholar]
68. Dumont NA, Wang YX, von Maltzahn J, Pasut A, Bentzinger CF. 68.  et al. 2015. Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nat. Med. 21:1455–63 [Google Scholar]
69. Needham M, Mastaglia FL. 69.  2016. Sporadic inclusion body myositis: a review of recent clinical advances and current approaches to diagnosis and treatment. Clin. Neurophysiol. 127:1764–73 [Google Scholar]
70. Rygiel KA, Miller J, Grady JP, Rocha MC, Taylor RW, Turnbull DM. 70.  2015. Mitochondrial and inflammatory changes in sporadic inclusion body myositis. Neuropathol. Appl. Neurobiol. 41:288–303 [Google Scholar]
71. Kim NC, Tresse E, Kolaitis RM, Molliex A, Thomas RE. 71.  et al. 2013. VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78:65–80 [Google Scholar]
72. Komatsu M, Kageyama S, Ichimura Y. 72.  2012. p62/SQSTM1/A170: physiology and pathology. Pharmacol. Res. 66:457–62 [Google Scholar]
73. Nogalska A, D'Agostino C, Engel WK, Davies KJ, Askanas V. 73.  2010. Decreased SIRT1 deacetylase activity in sporadic inclusion-body myositis muscle fibers. Neurobiol. Aging 31:1637–48 [Google Scholar]
74. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. 74.  2014. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 5:3557 [Google Scholar]
75. Moore SC, Patel AV, Matthews CE, Berrington de Gonzalez A, Park Y. 75.  et al. 2012. Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLOS Med 9:e1001335 [Google Scholar]
76. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K. 76.  et al. 2011. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17:179–88 [Google Scholar]
77. Houtkooper RH, Williams RW, Auwerx J. 77.  2010. Metabolic networks of longevity. Cell 142:9–14 [Google Scholar]
78. Cantó C, Menzies KJ, Auwerx J. 78.  2015. NAD⁺ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab 22:31–53 [Google Scholar]
79. Houtkooper RH, Cantó C, Wanders RJ, Auwerx J. 79.  2010. The secret life of NAD⁺: an old metabolite controlling new metabolic signaling pathways. Endocrine Rev 31:194–223 [Google Scholar]
80. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L. 80.  et al. 2009. AMPK regulates energy expenditure by modulating NAD⁺ metabolism and SIRT1 activity. Nature 458:1056–60 [Google Scholar]
81. Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D. 81.  et al. 2010. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285:8340–51 [Google Scholar]
82. Um JH, Park SJ, Kang H, Yang S, Foretz M. 82.  et al. 2010. AMP-activated protein kinase–deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59:554–63 [Google Scholar]
83. Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T. 83.  et al. 2013. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339:1216–19 [Google Scholar]
84. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C. 84.  et al. 2006. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–42 [Google Scholar]
85. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C. 85.  et al. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127:1109–22 [Google Scholar]
86. Moussa C, Hebron M, Huang X, Ahn J, Rissman RA. 86.  et al. 2017. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease. J. Neuroinflamm. 14:1 [Google Scholar]
87. Ahmed T, Javed S, Javed S, Tariq A, Šamec D. 87.  et al. 2016. Resveratrol and Alzheimer's disease: mechanistic insights. Mol. Neurobiol. 54:2622–35 [Google Scholar]
88. Douglas PM, Dillin A. 88.  2010. Protein homeostasis and aging in neurodegeneration. J. Cell Biol. 190:719–29 [Google Scholar]
89. Bonkowski MS, Sinclair DA. 89.  2016. Slowing ageing by design: the rise of NAD⁺ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17:679–90 [Google Scholar]
90. Brasnyó P, Molnár GA, Mohás M, Markó L, Laczy B. 90.  et al. 2011. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br. J. Nutr. 106:383–89 [Google Scholar]
91. Bhatt JK, Thomas S, Nanjan MJ. 91.  2012. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 32:537–41 [Google Scholar]
92. Timmers S, Auwerx J, Schrauwen P. 92.  2012. The journey of resveratrol from yeast to human. Aging 4:146–58 [Google Scholar]
93. Sandoval-Acuna C, Ferreira J, Speisky H. 93.  2014. Polyphenols and mitochondria: an update on their increasingly emerging ROS-scavenging independent actions. Arch. Biochem. Biophys. 559:75–90 [Google Scholar]
94. Kim J, Yang G, Kim Y, Kim J, Ha J. 94.  2016. AMPK activators: mechanisms of action and physiological activities. Exp. Mol. Med. 48:e224 [Google Scholar]
95. Thilakarathna SH, Rupasinghe HP. 95.  2013. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 5:3367–87 [Google Scholar]
96. Libri V, Brown AP, Gambarota G, Haddad J, Shields GS. 96.  et al. 2012. A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers. PLOS ONE 7:e51395 [Google Scholar]
97. Hoffmann E, Wald J, Lavu S, Roberts J, Beaumont C. 97.  et al. 2013. 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. 75:186–96 [Google Scholar]
98. Baksi A, Kraydashenko O, Zalevkaya A, Stets R, Elliott P. 98.  et al. 2014. A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes. Br. J. Clin. Pharmacol. 78:69–77 [Google Scholar]
99. Ryu D, Jo YS, Lo Sasso G, Stein S, Zhang H. 99.  et al. 2014. A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function. Cell Metab 20:856–69 [Google Scholar]
100. Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T. 100.  et al. 2008. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102:703–710 [Google Scholar]
101. Rardin MJ, He W, Nishida Y, Newman JC, Carrico C. 101.  et al. 2013. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 18:920–33 [Google Scholar]
102. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B. 102.  et al. 2010. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–25 [Google Scholar]
103. Sadhukhan S, Liu X, Ryu D, Nelson OD, Stupinski JA. 103.  et al. 2016. Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. PNAS 113:4320–25 [Google Scholar]
104. Someya S, Yu W, Hallows WC, Xu J, Vann JM. 104.  et al. 2010. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143:802–12 [Google Scholar]
105. Brown KD, Maqsood S, Huang JY, Pan Y, Harkcom W. 105.  et al. 2014. Activation of SIRT3 by the NAD⁺ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab 20:1059–68 [Google Scholar]
106. Hardie DG, Schaffer BE, Brunet A. 106.  2016. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol 26:190–201 [Google Scholar]
107. Ota S, Horigome K, Ishii T, Nakai M, Hayashi K. 107.  et al. 2009. Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem. Biophys. Res. Commun. 388:311–16 [Google Scholar]
108. Barzilai N, Crandall Jill P, Kritchevsky Stephen B, Espeland MA. 108.  2016. Metformin as a tool to target aging. Cell Metab 23:1060–65 [Google Scholar]
109. Faubert B, Vincent EE, Poffenberger MC, Jones RG. 109.  2015. The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer Lett 356:165–70 [Google Scholar]
110. Cheng J, Shuai X, Gao J, Cai M, Wang G, Tao K. 110.  2016. Prognostic significance of AMPK in human malignancies: a meta-analysis. Oncotarget 7:75739–48 [Google Scholar]
111. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL. 111.  et al. 2013. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4:2192 [Google Scholar]
112. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 112.  1995. 5-Aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells?. Eur. J. Biochem. 229:558–65 [Google Scholar]
113. Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO. 113.  2000. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88:2219–26 [Google Scholar]
114. Narkar VA, Downes M, Yu RT, Embler E, Wang YX. 114.  et al. 2008. AMPK and PPARδ agonists are exercise mimetics. Cell 134:405–15 [Google Scholar]
115. Vincent MF, Bontemps F, Van den Berghe G. 115.  1992. Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes. Biochem. J. 281:267 [Google Scholar]
116. Dixon R, Gourzis J, McDermott D, Fujitaki J, Dewland P, Gruber H. 116.  1991. AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent. J. Clin. Pharmacol. 31:342–47 [Google Scholar]
117. Pirkmajer S, Kulkarni SS, Tom RZ, Ross FA, Hawley SA. 117.  2015. Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation. Diabetes 64:360–69 [Google Scholar]
118. Asby DJ, Cuda F, Beyaert M, Houghton FD, Cagampang FR, Tavassoli A. 118.  2015. AMPK activation via modulation of de novo purine biosynthesis with an inhibitor of ATIC homodimerization. Chem. Biol. 22:838–48 [Google Scholar]
119. Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF. 119.  et al. 2013. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 4:3017 [Google Scholar]
120. Cool B, Zinker B, Chiou W, Kifle L, Cao N. 120.  et al. 2006. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3:403–16 [Google Scholar]
121. Lai YC, Kviklyte S, Vertommen D, Lantier L, Foretz M. 121.  et al. 2014. A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators. Biochem. J. 460:363–75 [Google Scholar]
122. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C. 122.  et al. 2012. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336:918–22 [Google Scholar]
123. Hunter RW, Foretz M, Bultot L, Fullerton MD, Deak M. 123.  et al. 2014. Mechanism of action of compound-13: an α1-selective small molecule activator of AMPK. Chem. Biol. 21:866–79 [Google Scholar]
124. Sidhu JS, Rajawat YS, Rami TG, Gollob MH, Wang Z. 124.  et al. 2005. Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome. Circulation 111:21–29 [Google Scholar]
125. Gollob MH, Seger JJ, Gollob TN, Tapscott T, Gonzales O. 125.  et al. 2001. Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy. Circulation 104:3030–33 [Google Scholar]
126. Zoncu R, Efeyan A, Sabatini DM. 126.  2011. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12:21–35 [Google Scholar]
127. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J. 127.  et al. 2010. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11:35–46 [Google Scholar]
128. Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD. 128.  et al. 2012. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15:713–24 [Google Scholar]
129. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM. 129.  et al. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–95 [Google Scholar]
130. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H. 130.  et al. 2014. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510:397–401 [Google Scholar]
131. Kim J, Kundu M, Viollet B, Guan K-L. 131.  2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13:132–41 [Google Scholar]
132. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA. 132.  et al. 2011. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–61 [Google Scholar]
133. Majumder S, Richardson A, Strong R, Oddo S. 133.  2011. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLOS ONE 6:e25416 [Google Scholar]
134. Yang SB, Tien AC, Boddupalli G, Xu AW, Jan YN, Jan LY. 134.  2012. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron 75:425–36 [Google Scholar]
135. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M. 135.  et al. 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335:1638–43 [Google Scholar]
136. Cantó C, Menzies KJ, Auwerx J. 136.  2015. NAD⁺ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab 22:31–53 [Google Scholar]
137. Houtkooper RH, Auwerx J. 137.  2012. Exploring the therapeutic space around NAD⁺. J. Cell Biol. 199:205–9 [Google Scholar]
138. Yang SJ, Choi JM, Kim L, Park SE, Rhee EJ. 138.  et al. 2014. Nicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes. J. Nutr. Biochem. 25:66–72 [Google Scholar]
139. Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH. 139.  et al. 2012. The NAD⁺ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15:838–47 [Google Scholar]
140. Yoshino J, Mills Kathryn F, Yoon MJ, Imai S-I. 140.  2011. Nicotinamide mononucleotide, a key NAD⁺ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 14:528–36 [Google Scholar]
141. Bender DA, Olufunwa R. 141.  1988. Utilization of tryptophan, nicotinamide and nicotinic acid as precursors for nicotinamide nucleotide synthesis in isolated rat liver cells. Br. J. Nutr. 59:279–87 [Google Scholar]
142. Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X. 142.  et al. 2015. Eliciting the mitochondrial unfolded protein response via NAD repletion reverses fatty liver disease. Hepatology 63:1190–204 [Google Scholar]
143. Khan NA, Auranen M, Paetau I, Pirinen E, Euro L. 143.  et al. 2014. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol. Med. 6:721–31 [Google Scholar]
144. Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh R. 144.  et al. 2015. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurol 15:19 [Google Scholar]
145. Wang X, Hu X, Yang Y, Takata T, Sakurai T. 145.  2016. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res 1643:1–9 [Google Scholar]
146. Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J. 146.  et al. 2014. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158:1324–34 [Google Scholar]
147. Sasaki Y, Araki T, Milbrandt J. 147.  2006. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J. Neurosci. 26:8484–91 [Google Scholar]
148. Wang L, Ding D, Salvi R, Roth JA. 148.  2014. Nicotinamide adenine dinucleotide prevents neuroaxonal degeneration induced by manganese in cochlear organotypic cultures. Neurotoxicology 40:65–74 [Google Scholar]
149. Trammell SAJ, Schmidt MS, Weidemann BJ, Redpath P2, Jaksch F. 149.  et al. 2016. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun. 7:12948 [Google Scholar]
150. Martire S, Mosca L, d'Erme M. 150.  2015. PARP-1 involvement in neurodegeneration: a focus on Alzheimer's and Parkinson's diseases. Mech. Ageing Dev. 146–148:53–64 [Google Scholar]
151. Cantó C, Sauve AA, Bai P. 151.  2013. Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol. Aspects Med. 34:1168–201 [Google Scholar]
152. Bai P, Cantó C, Oudart H, Brunyánszki A, Cen Y. 152.  et al. 2011. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13:461–68 [Google Scholar]
153. Gariani K, Ryu D, Menzies KJ, Yi HS, Stein S. 153.  et al. 2016. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J. Hepatol. 66:132–41 [Google Scholar]
154. Lehmann M, Pirinen E, Mirsaidi A, Kunze FA, Richards PJ. 154.  et al. 2015. ARTD1-induced poly-ADP-ribose formation enhances PPARγ ligand binding and co-factor exchange. Nucleic Acids Res 43:129–42 [Google Scholar]
155. Pirinen E, Cantó C, Jo YS, Morato L, Zhang H. 155.  et al. 2014. Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab 19:1034–41 [Google Scholar]
156. Mukhopadhyay P, Horváth B, Rajesh M, Varga ZV, Gariani K. 156.  et al. 2016. PARP inhibition protects against alcoholic and nonalcoholic steatohepatitis. J. Hepatol. 66:589–600 [Google Scholar]
157. Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA. 157.  et al. 2014. NAD⁺-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab 19:1042–49 [Google Scholar]
158. Martire S, Fuso A, Mosca L, Forte E, Correani V. 158.  et al. 2016. Bioenergetic impairment in animal and cellular models of Alzheimer's disease: PARP-1 inhibition rescues metabolic dysfunctions. J. Alzheimer's Dis. 54:307–24 [Google Scholar]
159. Outeiro TF, Grammatopoulos TN, Altmann S, Amore A, Standaert DG. 159.  et al. 2007. Pharmacological inhibition of PARP-1 reduces α-synuclein- and MPP⁺-induced cytotoxicity in Parkinson's disease in vitro models. Biochem. Biophys. Res. Commun. 357:596–602 [Google Scholar]
160. Lehmann S, Costa AC, Celardo I, Loh SHY, Martins LM. 160.  2016. Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson's disease. Cell Death Dis 7:e2166 [Google Scholar]
161. Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T. 161.  et al. 2014. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD⁺/SIRT1 reduction. Cell 157:882–96 [Google Scholar]
162. Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K. 162.  et al. 2016. NAD⁺ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab 24:566–81 [Google Scholar]
163. Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D. 163.  et al. 2013. The NAD⁺/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430–41 [Google Scholar]
164. Howard M, Grimaldi JC, Bazan JF, Lund FE, Santos-Argumedo L. 164.  et al. 1993. Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science 262:1056–59 [Google Scholar]
165. Hirata Y, Kimura N, Sato K, Ohsugi Y, Takasawa S. 165.  et al. 1994. ADP ribosyl cyclase activity of a novel bone marrow stromal cell surface molecule, BST-1. FEBS Lett 356:244–48 [Google Scholar]
166. Barbosa MTP, Soares SM, Novak CM, Sinclair D, Levine JA. 166.  et al. 2007. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J. 21:3629–39 [Google Scholar]
167. Camacho-Pereira J, Tarragó MG, Chini CC, Nin V, Escande C. 167.  et al. 2016. CD38 dictates age-related NAD Decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab 23:1127–39 [Google Scholar]
168. Polzonetti V, Carpi FM, Micozzi D, Pucciarelli S, Vincenzetti S, Napolioni V. 168.  2012. Population variability in CD38 activity: correlation with age and significant effect of TNF-α-308G>A and CD38 184C>G SNPs. Mol. Genet. Metab. 105:502–507 [Google Scholar]
169. Escande C, Nin V, Price NL, Capellini V, Gomes AP. 169.  et al. 2013. Flavonoid apigenin is an inhibitor of the NAD⁺ase CD38: implications for cellular NAD⁺ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62:1084–93 [Google Scholar]
170. Haffner CD, Becherer JD, Boros EE, Cadilla R, Carpenter T. 170.  et al. 2015. Discovery, synthesis, and biological evaluation of thiazoloquin(az)olin(on)es as potent CD38 inhibitors. J. Med. Chem. 58:3548–71 [Google Scholar]
171. Kraus D, Yang Q, Kong D, Banks AS, Zhang L. 171.  et al. 2014. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508:258–62 [Google Scholar]
172. Saito K, Fujigaki S, Heyes MP, Shibata K, Takemura M. 172.  et al. 2000. Mechanism of increases in l-kynurenine and quinolinic acid in renal insufficiency. Am. J. Physiol. Renal. Physiol. 279:F565–72 [Google Scholar]
173. Fukuwatari T, Ohsaki S, Fukuoka S-I, Sasaki R, Shibata K. 173.  2004. Phthalate esters enhance quinolinate production by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a key enzyme of the tryptophan pathway. Toxicol. Sci. 81:302–8 [Google Scholar]
174. Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK. 174.  et al. 2006. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev. 58:726 [Google Scholar]
175. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. 175.  1999. Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting. J. Clin. Investig. 103:1489–98 [Google Scholar]
176. Scott R, O'Brien R, Fulcher G, Pardy C, D'Emden M. 176.  et al. 2009. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 32:493–98 [Google Scholar]
177. Feng X, Gao X, Jia Y, Zhang H, Pan Q. 177.  et al. 2015. PPAR-α agonist fenofibrate decreased serum irisin levels in type 2 diabetes patients with hypertriglyceridemia. PPAR Res 2015:924131 [Google Scholar]
178. Leibowitz MD, Fiévet C, Hennuyer N, Peinado-Onsurbe J, Duez H. 178.  et al. 2000. Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Lett 473:333–36 [Google Scholar]
179. Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H. 179.  et al. 2003. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. PNAS 100:15924–29 [Google Scholar]
180. Fan W, Evans RM. 180.  2016. Exercise mimetics: impact on health and performance. Cell Metab 25:242–47 [Google Scholar]
181. Fan W, Waizenegger W, Lin CS, Sorrentino V, He MX. 181.  et al. 2017. PPARδ promotes running endurance by preserving glucose. Cell Metab 25:1186–93.e4 [Google Scholar]
182. Djouadi F, Aubey F, Schlemmer D, Ruiter JP, Wanders RJ. 182.  et al. 2005. 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. 14:2695–703 [Google Scholar]
183. Gobin-Limballe S, Djouadi F, Aubey F, Olpin S, Andresen BS. 183.  et al. 2007. 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. 81:1133–43 [Google Scholar]
184. Bonnefont JP, Bastin J, Laforêt P, Aubey F, Mogenet A. 184.  et al. 2010. Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency. Clin. Pharmacol. Ther. 88:101–8 [Google Scholar]
185. Kung J, Henry RR. 185.  2012. Thiazolidinedione safety. Expert Opin. Drug Saf. 11:565–79 [Google Scholar]
186. Picard F, Auwerx J. 186.  2002. PPARγ and glucose homeostasis. Annu. Rev. Nutr. 22:167–97 [Google Scholar]
187. Rocchi S, Picard F, Vamecq J, Gelman L, Potier N. 187.  et al. 2001. A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol. Cell 8:737–47 [Google Scholar]
188. Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ. 188.  et al. 2011. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature 477:477–81 [Google Scholar]
189. Li P, Fan W, Xu J, Lu M, Yamamoto H. 189.  et al. 2011. Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell 147:815–26 [Google Scholar]
190. Chandalia A, Clarke HJ, Clemens LE, Pandey B, Vicena V. 190.  et al. 2009. MBX-102/JNJ39659100, a novel non-TZD selective partial PPAR-γ agonist lowers triglyceride independently of PPAR-α activation. PPAR Res 2009:706852 [Google Scholar]
191. Chae S, Ahn BY, Byun K, Cho YM, Yu MH. 191.  et al. 2013. A systems approach for decoding mitochondrial retrograde signaling pathways. Sci. Signal. 6:rs4 [Google Scholar]
192. Lee SE, Koo YD, Lee JS, Kwak SH, Jung HS. 192.  et al. 2015. Retinoid X receptor α overexpression alleviates mitochondrial dysfunction-induced insulin resistance through transcriptional regulation of insulin receptor substrate 1. Mol. Cells 38:356–61 [Google Scholar]
193. Claudel T, Leibowitz MD, Fiévet C, Tailleux A, Wagner B. 193.  et al. 2001. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. PNAS 98:2610–15 [Google Scholar]
194. Giguère V. 194.  2008. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr. Rev. 29:677–96 [Google Scholar]
195. Rangwala SM, Wang X, Calvo JA, Lindsley L, Zhang Y. 195.  et al. 2010. Estrogen-related receptor γ is a key regulator of muscle mitochondrial activity and oxidative capacity. J. Biol. Chem. 285:22619–29 [Google Scholar]
196. Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J. 196.  et al. 2004. The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis. PNAS 101:6472–77 [Google Scholar]
197. Narkar VA, Fan W, Downes M, Yu RT, Jonker JW. 197.  et al. 2011. Exercise and PGC-1α-independent synchronization of type I muscle metabolism and vasculature by ERRγ. Cell Metab 13:283–93 [Google Scholar]
198. Zuercher WJ, Gaillard S, Orband-Miller LA, Chao EY, Shearer BG. 198.  et al. 2005. 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. 48:3107–9 [Google Scholar]
199. Kim Y, Koh M, Kim D-K, Choi H-S, Park SB. 199.  2009. Efficient discovery of selective small molecule agonists of estrogen-related receptor γ using combinatorial approach. J. Comb. Chem. 11:928–37 [Google Scholar]
200. Willy PJ, Murray IR, Qian J, Busch BB, Stevens WC Jr.. 200.  et al. 2004. Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand. PNAS 101:8912–17 [Google Scholar]
201. Chisamore MJ, Cunningham ME, Flores O, Wilkinson HA, Chen JD. 201.  2009. Characterization of a novel small molecule subtype specific estrogen-related receptor α antagonist in MCF-7 breast cancer cells. PLOS ONE 4:e5624 [Google Scholar]
202. Patch RJ, Searle LL, Kim AJ, De D, Zhu X. 202.  et al. 2011. Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents. J. Med. Chem. 54:788–808 [Google Scholar]
203. Zhao X, Hirota T, Han X, Cho H, Chong LW. 203.  et al. 2016. Circadian amplitude regulation via FBXW7-targeted REV-ERBα degradation. Cell 165:1644–57 [Google Scholar]
204. Cho H, Zhao X, Hatori M, Yu RT, Barish GD. 204.  et al. 2012. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485:123–27 [Google Scholar]
205. Renaud JP, Harris JM, Downes M, Burke LJ, Muscat GE. 205.  2000. Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains. Mol. Endocrinol. 14:700–17 [Google Scholar]
206. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR. 206.  et al. 2007. Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science 318:1786–89 [Google Scholar]
207. Garaulet M, Gomez-Abellan P. 207.  2014. Timing of food intake and obesity: a novel association. Physiol. Behav. 134:44–50 [Google Scholar]
208. Goumidi L, Grechez A, Dumont J, Cottel D, Kafatos A. 208.  et al. 2013. Impact of REV-ERB alpha gene polymorphisms on obesity phenotypes in adult and adolescent samples. Int. J. Obes. 37:666–72 [Google Scholar]
209. Woldt E, Sebti Y, Solt LA, Duhem C, Lancel S. 209.  et al. 2013. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat. Med. 19:1039–46 [Google Scholar]
210. Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ. 210.  et al. 2012. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485:62–68 [Google Scholar]
211. Kelly DP, Scarpulla RC. 211.  2004. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–68 [Google Scholar]
212. Collard J, Khorkova SO. 212.  2010. Treatment of nuclear respiratory factor 1 (NRF1) related diseases by inhibition of natural antisense transcript to NRF1 US Patent No. 20120264812
213. Iyer S, Thomas RR, Portell FR, Dunham LD, Quigley CK, Bennett JP Jr.. 213.  2009. Recombinant mitochondrial transcription factor A with N-terminal mitochondrial transduction domain increases respiration and mitochondrial gene expression. Mitochondrion 9:196–203 [Google Scholar]
214. Thomas RR, Khan SM, Smigrodzki RM, Onyango IG, Dennis J. 214.  et al. 2012. RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice. Aging 4:620–35 [Google Scholar]
215. Iyer S, Bergquist K, Young K, Gnaiger E, Rao RR, Bennett JP Jr.. 215.  2012. Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells. Hum. Gene Ther. 23:647–57 [Google Scholar]
216. Mouchiroud L, Eichner LJ, Shaw RJ, Auwerx J. 216.  2014. Transcriptional coregulators: fine-tuning metabolism. Cell Metab 20:26–40 [Google Scholar]
217. Cantó C, Auwerx J. 217.  2009. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20:98–105 [Google Scholar]
218. Puigserver P, Spiegelman BM. 218.  2003. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24:78–90 [Google Scholar]
219. Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H. 219.  et al. 2013. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 23:302–15 [Google Scholar]
220. Luo C, Lim JH, Lee Y, Granter SR, Thomas A. 220.  et al. 2016. A PGC1α-mediated transcriptional axis suppresses melanoma metastasis. Nature 537:422–26 [Google Scholar]
221. Barrow JJ, Balsa E, Verdeguer F, Tavares CD, Soustek MS. 221.  et al. 2016. Bromodomain inhibitors correct bioenergetic deficiency caused by mitochondrial disease complex I mutations. Mol. Cell 64:163–75 [Google Scholar]
222. Ye L, Kleiner S, Wu J, Sah R, Gupta RK. 222.  et al. 2012. TRPV4 is a regulator of adipose oxidative metabolism, inflammation and energy homeostasis. Cell 151:96–110 [Google Scholar]
223. Riera CE, Huising MO, Follett P, Leblanc M, Halloran J. 223.  et al. 2014. TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 157:1023–36 [Google Scholar]
224. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. 224.  2008. Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7:678–93 [Google Scholar]
225. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW. 225.  et al. 2006. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439:484–89 [Google Scholar]
226. Pellicciari R, Sato H, Gioiello A, Costantino G, Macchiarulo A. 226.  et al. 2007. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5. J. Med. Chem. 50:4265–68 [Google Scholar]
227. Pellicciari R, Gioiello A, Macchiarulo A, Thomas C, Rosatelli E. 227.  et al. 2009. 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. 52:7958–61 [Google Scholar]
228. Perino A, Schoonjans K. 228.  2015. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol. Sci. 36:847–57 [Google Scholar]
229. Fang S, Suh JM, Reilly SM, Yu E, Osborn O. 229.  et al. 2015. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21:159–65 [Google Scholar]
230. Picard F, Géhin M, Annicotte J, Rocchi S, Champy MF. 230.  et al. 2002. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111:931–41 [Google Scholar]
231. Coste A, Antal MC, Chan S, Kastner P, Mark M. 231.  et al. 2006. Absence of the steroid receptor coactivator-3 induces B-cell lymphoma. EMBO J 25:2453–64 [Google Scholar]
232. Jo Y-S, Ryu D, Maida A, Wang X, Evans RM. 232.  et al. 2015. Phosphorylation of the nuclear receptor co-repressor 1 by protein kinase B (PKB/Akt) switches its co-repressor targets in the liver. Hepatology 62:1606–18 [Google Scholar]
233. Pérez-Schindler J, Summermatter S, Salatino S, Zorzato F, Beer M. 233.  et al. 2012. The corepressor NCoR1 antagonizes PGC-1α and estrogen-related receptor α in the regulation of skeletal muscle function and oxidative metabolism. Mol. Cell. Biol. 32:4913–24 [Google Scholar]
234. Yamamoto H, Williams EG, Mouchiroud L, Cantó C, Fan W. 234.  et al. 2011. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147:827–39 [Google Scholar]
235. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. 235.  2010. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468:1100–4 [Google Scholar]
236. Iezzi S, Di Padova M, Serra C, Caretti G, Simone C. 236.  et al. 2004. Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin. Dev. Cell 6:673–84 [Google Scholar]
237. Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K. 237.  et al. 2002. The retinoblastoma-histone deacetylase 3 complex inhibits PPARγ and adipocyte differentiation. Dev. Cell 3:903–10 [Google Scholar]
238. Sun Z, Miller RA, Patel RT, Chen J, Dhir R. 238.  et al. 2012. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 18:934–42 [Google Scholar]
239. Debevec D, Christian M, Morganstein D, Seth A, Herzog B. 239.  et al. 2007. 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. 21:1581–92 [Google Scholar]
240. Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S. 240.  et al. 2004. Nuclear receptor corepressor RIP140 regulates fat accumulation. PNAS 101:8437–42 [Google Scholar]
241. Seth A, Steel JH, Nichol D, Pocock V, Kumaran MK. 241.  et al. 2007. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab 6:236–45 [Google Scholar]
242. Powelka AM, Seth A, Virbasius JV, Kiskinis E, Nicoloro SM. 242.  et al. 2006. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J. Clin. Investig. 116:125–36 [Google Scholar]
243. Rosell M, Jones MC, Parker MG. 243.  2011. Role of nuclear receptor corepressor RIP140 in metabolic syndrome. Biochim. Biophys. Acta 1812:919–28 [Google Scholar]
244. Blanchet E, Annicotte JS, Lagarrigue S, Aguilar V, Clapé C. 244.  et al. 2011. E2F transcription factor-1 regulates oxidative metabolism. Nat. Cell Biol. 13:1146–52 [Google Scholar]
245. Scimè A, Grenier G, Huh MS, Gillespie MA, Bevilacqua L. 245.  et al. 2005. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-α. Cell Metab 2:283–95 [Google Scholar]
246. Calo E, Quintero-Estades JA, Danielian PS, Nedelcu S, Berman SD, Lees JA. 246.  2010. Rb regulates fate choice and lineage commitment in vivo. Nature 466:1110–14 [Google Scholar]
247. Dali-Youcef N, Mataki C, Coste A, Messaddeq N, Giroud S. 247.  et al. 2007. Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure. PNAS 104:10703–708 [Google Scholar]
248. Blanchet E, Annicotte JS, Pradelli LA, Hugon G, Matecki S. 248.  et al. 2012. E2F transcription factor-1 deficiency reduces pathophysiology in the mouse model of Duchenne muscular dystrophy through increased muscle oxidative metabolism. Hum. Mol. Genet. 21:3910–17 [Google Scholar]
249. White R, Leonardsson G, Rosewell I, Jacobs MA, Milligan S, Parker M. 249.  et al. 2000. The nuclear receptor co-repressor Nrip1 (RIP140) is essential for female fertility. Nat. Med. 6:1368–74 [Google Scholar]
250. Tainter ML, Stockton AB, Cutting WC. 250.  1935. Dinitrophenol in the treatment of obesity: final report. J. Am. Med. Assoc. 105:332–37 [Google Scholar]
251. Perry RJ, Kim T, Zhang XM, Lee HY, Pesta D. 251.  et al. 2013. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab 18:740–48 [Google Scholar]
252. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. 252.  2015. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347:1253–56 [Google Scholar]
253. Sena LA, Chandel NS. 253.  2012. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48:158–67 [Google Scholar]
254. Song B-J, Akbar M, Abdelmegeed MA, Byun K, Lee B. 254.  et al. 2014. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol 3:109–23 [Google Scholar]
255. Butterfield DA, Di Domenico F, Swomley Aaron M, Head E, Perluigi M. 255.  2014. Redox proteomics analysis to decipher the neurobiology of Alzheimer-like neurodegeneration: overlaps in Down's syndrome and Alzheimer's disease brain. Biochem. J. 463:177 [Google Scholar]
256. Murphy MP, Smith RAJ. 256.  2007. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu. Rev. Pharmacol. Toxicol. 47:629–56 [Google Scholar]
257. Szeto HH. 257.  2006. Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS J 8:E277–83 [Google Scholar]
258. Nickel A, Kohlhaas M, Maack C. 258.  2014. Mitochondrial reactive oxygen species production and elimination. J. Mol. Cell Cardiol. 73:26–33 [Google Scholar]
259. Szeto HH. 259.  2014. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 171:2029–50 [Google Scholar]
260. Szeto HH, Schiller PW. 260.  2011. Novel therapies targeting inner mitochondrial membrane—from discovery to clinical development. Pharm. Res. 28:2669–79 [Google Scholar]
261. Wai T, Langer T. 261.  2016. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol. Metab. 27:105–17 [Google Scholar]
262. Jheng H-F, Tsai PJ, Guo SM, Kuo LH, Chang CS. 262.  et al. 2012. Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol. Cell. Biol. 32:309–19 [Google Scholar]
263. Parone PA, Da Cruz S, Tondera D, Mattenberger Y, James DI. 263.  et al. 2008. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLOS ONE 3:e3257 [Google Scholar]
264. Bach D, Pich S, Soriano FX, Vega N, Baumgartner B. 264.  et al. 2003. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity. J. Biol. Chem. 278:17190–97 [Google Scholar]
265. Sebastián D, Hernández-Alvarez MI, Segalés J, Sorianello E, Muñoz JP. 265.  et al. 2012. Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. PNAS 109:5523–28 [Google Scholar]
266. Kulkarni SS, Joffraud M, Boutant M, Ratajczak J, Gao AW. 266.  et al. 2016. Mfn1 deficiency in the liver protects against diet-induced insulin resistance and enhances the hypoglycemic effect of metformin. Diabetes 65:3552 [Google Scholar]
267. de Brito OM, Scorrano L. 267.  2008. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–10 [Google Scholar]
268. Wang X, Su B, Lee HG, Li X, Perry G. 268.  et al. 2009. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J. Neurosci. 29:9090–103 [Google Scholar]
269. Itoh K, Nakamura K, Iijima M, Sesaki H. 269.  2013. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23:64–71 [Google Scholar]
270. Wang D, Wang J, Bonamy GM, Meeusen S, Brusch RG. 270.  et al. 2012. A small molecule promotes mitochondrial fusion in mammalian cells. Angew. Chem. Int. Ed. 51:9302–5 [Google Scholar]
271. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C. 271.  et al. 2008. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev. Cell 14:193–204 [Google Scholar]
272. Yue W, Chen Z, Liu H, Yan C, Chen M. 272.  et al. 2014. A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res 24:482–96 [Google Scholar]
273. Qi X, Qvit N, Su Y-C, Mochly-Rosen D. 273.  2013. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J. Cell Sci. 126:789–802 [Google Scholar]
274. Ong S-B, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ. 274.  2010. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–22 [Google Scholar]
275. Gao D, Zhang L, Dhillon R, Hong TT, Shaw RM, Zhu J. 275.  2013. Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart. PLOS ONE 8:e60967 [Google Scholar]
276. Liot G, Bossy B, Lubitz S, Kushnareva Y, Sejbuk N, Bossy-Wetzel E. 276.  2009. Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Cell Death Differ 16:899–909 [Google Scholar]
277. Makino A, Scott BT, Dillmann WH. 277.  2010. Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 53:1783–94 [Google Scholar]
278. Maro B, Bornens M. 278.  1982. Reorganization of HeLa cell cytoskeleton induced by an uncoupler of oxidative phosphorylation. Nature 295:334–36 [Google Scholar]
279. Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E. 279.  et al. 2013. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497:451–57 [Google Scholar]
280. Jang SY, Kang HT, Hwang ES. 280.  2012. Nicotinamide-induced mitophagy: event mediated by high NAD⁺/NADH ratio and SIRT1 protein activation. J. Biol. Chem. 287:19304–14 [Google Scholar]
281. Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N. 281.  et al. 2016. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22:879–88 [Google Scholar]
282. Khaminets A, Behl C, Dikic I. 282.  2016. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol 26:6–16 [Google Scholar]
283. Narendra D, Tanaka A, Suen D-F, Youle RJ. 283.  2008. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183:795–803 [Google Scholar]
284. Narendra DP, Jin SM, Suen D-F, Gautier CA, Shen J. 284.  et al. 2010. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLOS Biol 8:e1000298 [Google Scholar]
285. Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ. 285.  2010. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191:933–42 [Google Scholar]
286. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA. 286.  et al. 2010. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLOS Biol 8:e1000298 [Google Scholar]
287. Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS. 287.  et al. 2014. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser⁶⁵. Biochem. J. 460:127–39 [Google Scholar]
288. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C. 288.  et al. 2015. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–14 [Google Scholar]
289. Rojansky R, Cha MY, Chan DC. 289.  2016. Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. eLife 5:e17896 [Google Scholar]
290. Al Rawi S, Louvet-Vallée S, Djeddi A, Sachse M, Culetto E. 290.  et al. 2011. Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission. Science 334:1144–47 [Google Scholar]
291. Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT. 291.  et al. 2008. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454:232–35 [Google Scholar]
292. Gao F, Chen D, Si J, Hu Q, Qin Z. 292.  et al. 2015. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum. Mol. Genet. 24:2528–38 [Google Scholar]
293. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH. 293.  et al. 2008. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283:10892–903 [Google Scholar]
294. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D. 294.  et al. 2009. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell Biol. 29:2570–81 [Google Scholar]
295. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH. 295.  et al. 2008. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 283:10892–903 [Google Scholar]
296. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D. 296.  et al. 2009. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell. Biol. 29:2570–81 [Google Scholar]
297. Liu L, Feng D, Chen G, Chen M, Zheng Q. 297.  et al. 2012. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat. Cell Biol. 14:177–85 [Google Scholar]
298. Palikaras K, Lionaki E, Tavernarakis N. 298.  2015. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521:525–28 [Google Scholar]
299. Georgakopoulos ND, Wells G, Campanella M. 299.  2017. The pharmacological regulation of cellular mitophagy. Nat. Chem. Biol. 13:136–46 [Google Scholar]
300. Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RLA. 300.  et al. 2010. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. PNAS 107:378–83 [Google Scholar]
301. Durcan TM, Fon EA. 301.  2015. The three ‘P's of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev 29:989–99 [Google Scholar]
302. Hertz NT, Berthet A, Sos ML, Thorn KS, Burlingame AL. 302.  et al. 2013. A neo-substrate that amplifies catalytic activity of parkinson's-disease-related kinase PINK1. Cell 154:737–47 [Google Scholar]
303. Allen GF, Toth R, James J, Ganley IG. 303.  2013. Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep 14:1127–35 [Google Scholar]
304. Park SJ, Shin JH, Kim ES, Jo YK, Kim JH. 304.  et al. 2012. Mitochondrial fragmentation caused by phenanthroline promotes mitophagy. FEBS Lett 586:4303–10 [Google Scholar]
305. Schiavi A, Maglioni S, Palikaras K, Shaik A, Strappazzon F. 305.  et al. 2015. Iron-starvation-induced mitophagy mediates lifespan extension upon mitochondrial stress in C. elegans. Curr. Biol. 25:1810–22 [Google Scholar]
306. Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D. 306.  2013. Bioavailable copper modulates oxidative phosphorylation and growth of tumors. PNAS 110:19507–12 [Google Scholar]
307. Matlack KE, Tardiff DF, Narayan P, Hamamichi S, Caldwell KA. 307.  et al. 2014. Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity. PNAS 111:4013–18 [Google Scholar]
308. Xu W, Barrientos T, Mao L, Rockman HA, Sauve AA, Andrews NC. 308.  2015. Lethal cardiomyopathy in mice lacking transferrin receptor in the heart. Cell Rep 13:533–45 [Google Scholar]
309. Arun B, Akar U, Gutierrez-Barrera AM, Hortobagyi GN, Ozpolat B. 309.  2015. The PARP inhibitor AZD2281 (Olaparib) induces autophagy/mitophagy in BRCA1 and BRCA2 mutant breast cancer cells. Int. J. Oncol. 47:262–68 [Google Scholar]
310. Kang HT, Hwang ES. 310.  2009. Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Aging Cell 8:426–38 [Google Scholar]
311. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K. 311.  et al. 2010. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Investig. 120:1043–55 [Google Scholar]
312. Quiros PM, Mottis A, Auwerx J. 312.  2016. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17:213–26 [Google Scholar]
313. Jovaisaite V, Mouchiroud L, Auwerx J. 313.  2014. The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease. J. Exp. Biol. 217:137–43 [Google Scholar]
314. Durieux J, Wolff S, Dillin A. 314.  2011. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144:79–91 [Google Scholar]
315. Horibe T, Hoogenraad NJ. 315.  2007. The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response. PLOS ONE 2:e835 [Google Scholar]
316. Zhao Q, Wang J, Levichkin IV, Stasinopoulos S, Ryan MT, Hoogenraad NJ. 316.  2002. A mitochondrial specific stress response in mammalian cells. EMBO J 21:4411–19 [Google Scholar]
317. Wu Y, Williams EG, Dubuis S, Mottis A, Jovaisaite V. 317.  et al. 2014. Multilayered genetics and omics dissection of mitochondrial activity in a mouse reference population. Cell 158:1415–30 [Google Scholar]
318. Wang X, Pandey AK, Mulligan MK, Williams EG, Mozhui K. 318.  et al. 2016. Joint mouse–human phenome-wide association to test gene function and disease risk. Nat. Commun. 7:10464 [Google Scholar]
319. Khan NA, Auranen M, Paetau I, Pirinen E, Euro L. 319.  et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.. EMBO Mol. Med. 6:721–31 [Google Scholar]
320. Mohrin M, Shin J, Liu Y, Brown K, Luo H. 320.  et al. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347:1374–77 [Google Scholar]
321. Song M, Mihara K, Chen Y, Scorrano L, Dorn GW II. 321.  2015. Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab 21:273–85 [Google Scholar]
322. Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Jordan SD. 322.  et al. 2016. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165:1209–23 [Google Scholar]
323. Papa L, Germain D. 323.  2011. Estrogen receptor mediates a distinct mitochondrial unfolded protein response. J. Cell Sci. 124:1396–402 [Google Scholar]
324. Tan K, Fujimoto M, Takii R, Takaki E, Hayashida N, Nakai A. 324.  2015. Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity. Nat. Commun. 6:6580 [Google Scholar]
325. Kim HE, Grant AR, Simic MS, Kohnz RA, Nomura DK. 325.  et al. 2016. Lipid biosynthesis coordinates a mitochondrial-to-cytosolic stress response. Cell 166:1539–52 [Google Scholar]
326. Wrobel L, Topf U, Bragoszewski P, Wiese S, Sztolsztener ME. 326.  et al. 2015. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524:485–88 [Google Scholar]
327. Kirstein-Miles J, Morimoto RI. 327.  2010. Caenorhabditis elegans as a model system to study intercompartmental proteostasis: interrelation of mitochondrial function, longevity, and neurodegenerative diseases. Dev. Dyn. 239:1529–38 [Google Scholar]
328. Senft D, Ronai ZA. 328.  2015. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem. Sci. 40:141–48 [Google Scholar]
329. Filippov V, Song MA, Zhang K, Vinters HV, Tung S. 329.  et al. 2012. Increased ceramide in brains with Alzheimer's and other neurodegenerative diseases. J. Alzheimer's Dis. 29:537–47 [Google Scholar]
330. Indiveri C, Iacobazzi V, Tonazzi A, Giangregorio N, Infantino V. 330.  et al. 2011. The mitochondrial carnitine/acylcarnitine carrier: function, structure and physiopathology. Mol. Aspects Med. 32:223–33 [Google Scholar]
331. Gulbins E. 331.  et al. 2013. Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat. Med. 19:934–38 [Google Scholar]
332. Teichgräber V, Ulrich M, Endlich N, Riethmüller J, Wilker B. 332.  et al. 2008. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat. Med. 14:382–91 [Google Scholar]
333. Kambe Y, Miyata A. 333.  2015. Potential involvement of the mitochondrial unfolded protein response in depressive-like symptoms in mice. Neurosci. Lett. 588:166–71 [Google Scholar]
334. Siegelin MD, Dohi T, Raskett CM, Orlowski GM, Powers CM. 334.  et al. 2011. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J. Clin. Investig. 121:1349–60 [Google Scholar]
335. Chung HK, Ryu D, Kim KS, Chang JY, Kim YK. 335.  et al. 2017. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J. Cell Biol. 216:149–65 [Google Scholar]
336. Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG. 336.  et al. 2015. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep 10:1681–91 [Google Scholar]
337. 337.  Deleted in proof
338. Orsucci D, Mancuso M, Filosto M, Siciliano G. 338.  2012. Tetracyclines and neuromuscular disorders. Curr. Neuropharmacol. 10:134–38 [Google Scholar]
339. Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH. 339.  et al. 2004. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J. Am. Geriatr. Soc. 52:381–87 [Google Scholar]
340. Suomalainen A, Elo JM, Pietiläinen KH, Hakonen AH, Sevastianova K. 340.  et al. 2011. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 10:806–18 [Google Scholar]
341. Renna M, Jimenez-Sanchez M, Sarkar S, Rubinsztein DC. 341.  2010. Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. J. Biol. Chem. 285:11061–67 [Google Scholar]
342. Balgi AD, Fonseca BD, Donohue E, Tsang TC, Lajoie P. 342.  et al. 2009. Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLOS ONE 4:e7124 [Google Scholar]
343. Schumacher JD, Guo GL. 343.  2015. Mechanistic review of drug-induced steatohepatitis. Toxicol. Appl. Pharmacol. 289:40–47 [Google Scholar]
344. Miyake Y, Kozutsumi Y, Nakamura S, Fujita T, Kawasaki T. 344.  1995. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochem. Biophys. Res. Commun. 211:396–403 [Google Scholar]
345. Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C. 345.  et al. 2010. Functional inhibitors of acid sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. Cell Physiol. Biochem. 26:9–20 [Google Scholar]
346. Glaros EN, Kim WS, Quinn CM, Jessup W, Rye KA, Garner B. 346.  2008. Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice. J. Lipid Res. 49:324–31 [Google Scholar]
347. Schmitz-Peiffer C. 347.  2010. Targeting ceramide synthesis to reverse insulin resistance. Diabetes 59:2351–53 [Google Scholar]
348. Ross JM, Olson L, Coppotelli G. 348.  2015. Mitochondrial and ubiquitin proteasome system dysfunction in ageing and disease: two sides of the same coin?. Int. J. Mol. Sci. 16:19458–76 [Google Scholar]
349. Lee BH, Lee MJ, Park S, Oh DC, Elsasser S. 349.  et al. 2010. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467:179–84 [Google Scholar]
350. Lee JH, Shin SK, Jiang Y, Choi WH, Hong C. 350.  et al. 2015. Facilitated tau degradation by USP14 aptamers via enhanced proteasome activity. Sci. Rep. 5:10757 [Google Scholar]
351. Shao LW, Niu R, Liu Y. 351.  2016. Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. Cell Res 26:1182–96 [Google Scholar]
352. Berendzen KM, Durieux J, Shao LW, Tian Y, Kim HE. 352.  et al. 2016. Neuroendocrine coordination of mitochondrial stress signaling and proteostasis. Cell 166:1553–63 [Google Scholar]
353. Copeland JM, Cho J, Lo T Jr., Hur JH, Bahadorani S. 353.  et al. 2009. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19:1591–98 [Google Scholar]
354. Owusu-Ansah E, Song W, Perrimon N. 354.  2013. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155:699–712 [Google Scholar]
355. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A. 355.  et al. 2015. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 21:443–54 [Google Scholar]
356. Chai GS, Duan DX, Ma RH, Shen JY, Li HL. 356.  et al. 2014. Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats. Neurosci. Bull. 30:923–35 [Google Scholar]
357. Lee C, Yen K, Cohen P. 357.  2013. Humanin: a harbinger of mitochondrial-derived peptides?. Trends Endocrinol. Metab. 24:222–28 [Google Scholar]
358. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkilä S, Wenz T. 358.  et al. 2010. Mitochondrial myopathy induces a starvation-like response. Hum. Mol. Genet. 19:3948–58 [Google Scholar]
359. Chau MDL, Gao J, Yang Q, Wu Z, Gromada J. 359.  2010. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway. PNAS 107:12553–58 [Google Scholar]
360. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L. 360.  et al. 2012. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–68 [Google Scholar]
361. Safdar A, Saleem A, Tarnopolsky MA. 361.  2016. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat. Rev. Endocrinol. 12:504–17 [Google Scholar]