Multisystem metabolic disorders caused by defects in oxidative phosphorylation (OXPHOS) are severe, often lethal, conditions. Inborn errors of OXPHOS function are termed primary mitochondrial disorders (PMDs), and the use of nutritional interventions is routine in their supportive management. However, detailed mechanistic understanding and evidence for efficacy and safety of these interventions are limited. Preclinical cellular and animal model systems are important tools to investigate PMD metabolic mechanisms and therapeutic strategies. This review assesses the mechanistic rationale and experimental evidence for nutritional interventions commonly used in PMDs, including micronutrients, metabolic agents, signaling modifiers, and dietary regulation, while highlighting important knowledge gaps and impediments for randomized controlled trials. Cellular and animal model systems that recapitulate mutations and clinical manifestations of specific PMDs are evaluated for their potential in determining pathological mechanisms, elucidating therapeutic health outcomes, and investigating the value of nutritional interventions for mitochondrial disease conditions.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL. 1.  et al. 2015. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann. Neurol. 77:753–59 [Google Scholar]
  2. Chinnery PF, Turnbull DM. 2.  2001. Epidemiology and treatment of mitochondrial disorders. Am. J. Med. Genet. 106:94–101 [Google Scholar]
  3. Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM. 3.  et al. 2015. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet. Med. 17:689–701 [Google Scholar]
  4. Camp KM, Krotoski D, Parisi MA, Gwinn KA, Cohen BH. 4.  et al. 2016. Nutritional interventions in primary mitochondrial disorders: developing an evidence base. Mol. Genet. Metab. 119:187–206 [Google Scholar]
  5. Chinnery P, Majamaa K, Turnbull D, Thorburn D. 5.  2006. Treatment for mitochondrial disorders. Cochrane Database Syst. Rev. 2006:1CD004426 [Google Scholar]
  6. Karaa A, Kriger J, Grier J, Holbert A, Thompson JL. 6.  et al. 2016. Mitochondrial disease patients' perception of dietary supplements' use. Mol. Genet. Metab. 119:100–8 [Google Scholar]
  7. Brown G. 7.  2014. Defects of thiamine transport and metabolism. J. Inherit. Metab. Dis. 37:577–85 [Google Scholar]
  8. Alfadhel M, Almuntashri M, Jadah RH, Bashiri FA, Al Rifai MT. 8.  et al. 2013. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J. Rare Dis. 8:83 [Google Scholar]
  9. Tabarki B, Al-Shafi S, Al-Shahwan S, Azmat Z, Al-Hashem A. 9.  et al. 2013. Biotin-responsive basal ganglia disease revisited: clinical, radiologic, and genetic findings. Neurology 80:261–67 [Google Scholar]
  10. Horvath R. 10.  2012. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ10). J. Inherit. Metab. Dis. 35:679–87 [Google Scholar]
  11. Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH. 11.  et al. 2009. A modern approach to the treatment of mitochondrial disease. Curr. Treat Options Neurol. 11:414–30 [Google Scholar]
  12. Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL. 12.  et al. 2011. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J. Inherit. Metab. Dis. 34:159–64 [Google Scholar]
  13. Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S. 13.  et al. 2010. Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in C20orf54. . Am. J. Hum. Genet. 86:485–89 [Google Scholar]
  14. Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M. 14.  et al. 2007. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130:2045–54 [Google Scholar]
  15. Gerards M, van den Bosch BJ, Danhauser K, Serre V, van Weeghel M. 15.  et al. 2011. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain 134:210–19 [Google Scholar]
  16. Garone C, Donati MA, Sacchini M, Garcia-Diaz B, Bruno C. 16.  et al. 2013. Mitochondrial encephalomyopathy due to a novel mutation in ACAD9. . JAMA Neurol 70:1177–79 [Google Scholar]
  17. Bernsen PL, Gabreels FJ, Ruitenbeek W, Hamburger HL. 17.  1993. Treatment of complex I deficiency with riboflavin. J. Neurol. Sci. 118:181–87 [Google Scholar]
  18. Penn AM, Lee JW, Thuillier P, Wagner M, Maclure KM. 18.  et al. 1992. MELAS syndrome with mitochondrial tRNALeu[UUR] mutation: correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Neurology 42:2147–52 [Google Scholar]
  19. Bugiani M, Lamantea E, Invernizzi F, Moroni I, Bizzi A. 19.  et al. 2006. Effects of riboflavin in children with complex II deficiency. Brain Dev 28:576–81 [Google Scholar]
  20. Artuch R, Vilaseca MA, Pineda M. 20.  1998. Biochemical monitoring of the treatment in paediatric patients with mitochondrial disease. J. Inherit. Metab. Dis. 21:837–45 [Google Scholar]
  21. Matthews PM, Ford B, Dandurand RJ, Eidelman DH, O'Connor D. 21.  et al. 1993. Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology 43:884–90 [Google Scholar]
  22. Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. 22.  2012. Treatment for mitochondrial disorders. Cochrane Database Syst. Rev. 2012:4CD004426 [Google Scholar]
  23. Bogan KL, Brenner C. 23.  2008. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr. 28:115–30 [Google Scholar]
  24. Belenky P, Bogan KL, Brenner C. 24.  2007. NAD+ metabolism in health and disease. Trends Biochem. Sci. 32:12–19 [Google Scholar]
  25. Falk MJ, Zhang Z, Rosenjack JR, Nissim I, Daikhin E. 25.  et al. 2008. Metabolic pathway profiling of mitochondrial respiratory chain mutants in C. . elegans. Mol. Genet. Metab. 93:388–97 [Google Scholar]
  26. Tischner C, Wenz T. 26.  2015. Keep the fire burning: current avenues in the quest of treating mitochondrial disorders. Mitochondrion 24:32–49 [Google Scholar]
  27. Hyland K, Shoffner J, Heales SJ. 27.  2010. Cerebral folate deficiency. J. Inherit. Metab. Dis. 33:563–70 [Google Scholar]
  28. Serrano M, Perez-Duenas B, Montoya J, Ormazabal A, Artuch R. 28.  2012. Genetic causes of cerebral folate deficiency: clinical, biochemical and therapeutic aspects. Drug Discov. Today 17:1299–306 [Google Scholar]
  29. Pineda M, Ormazabal A, Lopez-Gallardo E, Nascimento A, Solano A. 29.  et al. 2006. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann. Neurol. 59:394–98 [Google Scholar]
  30. Morris SM Jr.. 30.  2007. Arginine metabolism: boundaries of our knowledge. J. Nutr. 137:1602S–9S [Google Scholar]
  31. Chai J, Luo L, Hou F, Fan X, Yu J. 31.  et al. 2016. Agmatine reduces lipopolysaccharide-mediated oxidant response via activating PI3K/Akt pathway and up-regulating Nrf2 and HO-1 expression in macrophages. PLOS ONE 11:e0163634 [Google Scholar]
  32. Nissim I, Horyn O, Daikhin Y, Chen P, Li C. 32.  et al. 2014. The molecular and metabolic influence of long term agmatine consumption. J. Biol. Chem. 289:9710–29 [Google Scholar]
  33. Koga Y, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T. 33.  2010. MELAS and l-arginine therapy: pathophysiology of stroke-like episodes. Ann. N. Y. Acad. Sci. 1201:104–10 [Google Scholar]
  34. El-Hattab AW, Hsu JW, Emrick LT, Wong LJ, Craigen WJ. 34.  et al. 2012. Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Mol. Genet. Metab. 105:607–14 [Google Scholar]
  35. Siddiq I, Widjaja E, Tein I. 35.  2015. Clinical and radiologic reversal of stroke-like episodes in MELAS with high-dose l-arginine. Neurology 85:197–98 [Google Scholar]
  36. El-Hattab AW, Emrick LT, Williamson KC, Craigen WJ, Scaglia F. 36.  2013. The effect of citrulline and arginine supplementation on lactic acidemia in MELAS syndrome. Meta Gene 1:8–14 [Google Scholar]
  37. Rodan LH, Wells GD, Banks L, Thompson S, Schneiderman JE, Tein I. 37.  2015. L-arginine affects aerobic capacity and muscle metabolism in MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. PLOS ONE 10:e0127066 [Google Scholar]
  38. El-Hattab AW, Scaglia F. 38.  2015. Disorders of carnitine biosynthesis and transport. Mol. Genet. Metab. 116:107–12 [Google Scholar]
  39. Li JL, Wang QY, Luan HY, Kang ZC, Wang CB. 39.  2012. Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha. J. Biomed. Sci. 19:32 [Google Scholar]
  40. Ribas GS, Vargas CR, Wajner M. 40.  2014. l-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 533:469–76 [Google Scholar]
  41. DiMauro S, Hirano M, Schon EA. 41.  2006. Approaches to the treatment of mitochondrial diseases. Muscle Nerve 34:265–83 [Google Scholar]
  42. Stanley CA. 42.  2004. Carnitine deficiency disorders in children. Ann. N. Y. Acad. Sci. 1033:42–51 [Google Scholar]
  43. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E. 43.  et al. 2013. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19:576–85 [Google Scholar]
  44. Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N. 44.  et al. 2015. Creatine biosynthesis and transport in health and disease. Biochimie 119:146–65 [Google Scholar]
  45. Harris RC, Soderlund K, Hultman E. 45.  1992. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 83:367–74 [Google Scholar]
  46. Tarnopolsky MA, Parise G. 46.  1999. Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve 22:1228–33 [Google Scholar]
  47. DeBrosse C, Nanga RP, Wilson N, D'Aquilla K, Elliott M. 47.  et al. 2016. Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders. JCI Insight 1:e88207 [Google Scholar]
  48. Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. 48.  2007. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 35:235–42 [Google Scholar]
  49. Rauchova H, Drahota Z, Lenaz G. 49.  1995. Function of coenzyme Q in the cell: some biochemical and physiological properties. Physiol. Res. 44:209–16 [Google Scholar]
  50. Ernster L, Dallner G. 50.  1995. Biochemical, physiological and medical aspects of ubiquinone function. Biochim. Biophys. Acta 1271:195–204 [Google Scholar]
  51. Duncan AJ, Heales SJ, Mills K, Eaton S, Land JM, Hargreaves IP. 51.  2005. Determination of coenzyme Q10 status in blood mononuclear cells, skeletal muscle, and plasma by HPLC with di-propoxy-coenzyme Q10 as an internal standard. Clin. Chem. 51:2380–82 [Google Scholar]
  52. Tarnopolsky MA. 52.  2008. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv. Drug Deliv. Rev. 60:1561–67 [Google Scholar]
  53. Hargreaves IP. 53.  2014. Coenzyme Q10 as a therapy for mitochondrial disease. Int. J. Biochem. Cell Biol. 49:105–11 [Google Scholar]
  54. Haas RH. 54.  2007. The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease. Mitochondrion 7:Suppl.S136–45 [Google Scholar]
  55. Scalori V, Alessandri MG, Giovannini L, Bertelli A. 55.  1990. Plasma and tissue concentrations of coenzyme Q10 in the rat after intravenous, oral and topical administrations. Int. J. Tissue React. 12:149–54 [Google Scholar]
  56. Lass A, Forster MJ, Sohal RS. 56.  1999. Effects of coenzyme Q10 and α-tocopherol administration on their tissue levels in the mouse: elevation of mitochondrial α-tocopherol by coenzyme Q10. Free Radic. Biol. Med. 26:1375–82 [Google Scholar]
  57. Dorsam B, Fahrer J. 57.  2016. The disulfide compound α-lipoic acid and its derivatives: a novel class of anticancer agents targeting mitochondria. Cancer Lett 371:12–19 [Google Scholar]
  58. Wada H, Shintani D, Ohlrogge J. 58.  1997. Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. PNAS 94:1591–96 [Google Scholar]
  59. Rochette L, Ghibu S, Muresan A, Vergely C. 59.  2015. Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes. Can. J. Physiol. Pharmacol. 93:1021–27 [Google Scholar]
  60. Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C. 60.  2013. Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential. Mol. Nutr. Food Res. 57:114–25 [Google Scholar]
  61. Borowczyk K, Krawczyk M, Kubalczyk P, Chwatko G. 61.  2015. Determination of lipoic acid in biological samples. Bioanalysis 7:1785–98 [Google Scholar]
  62. Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. 62.  2007. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 35:235–42 [Google Scholar]
  63. Gomes MB, Negrato CA. 63.  2014. α-Lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol. Metab. Syndr. 6:80 [Google Scholar]
  64. Pashaj A, Xia M, Moreau R. 64.  2015. α-Lipoic acid as a triglyceride-lowering nutraceutical. Can. J. Physiol. Pharmacol. 93:1029–41 [Google Scholar]
  65. Jardim FR, de Rossi FT, Nascimento MX, da Silva Barros RG, Borges PA. 65.  et al. 2017. Resveratrol and brain mitochondria: a review. Mol. Neurobiol. In press. https://doi.org/10.1007/s12035-017-0448-z [Crossref] [Google Scholar]
  66. Viscomi C, Bottani E, Zeviani M. 66.  2015. Emerging concepts in the therapy of mitochondrial disease. Biochim. Biophys. Acta 1847:544–57 [Google Scholar]
  67. Sugden MC, Caton PW, Holness MJ. 67.  2010. PPAR control: It's SIRTainly as easy as PGC. J. Endocrinol. 204:93–104 [Google Scholar]
  68. Park SJ, Ahmad F, Philp A, Baar K, Williams T. 68.  et al. 2012. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148:421–33 [Google Scholar]
  69. Beher D, Wu J, Cumine S, Kim KW, Lu SC. 69.  et al. 2009. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem. Biol. Drug Des. 74:619–24 [Google Scholar]
  70. Lopes Costa A, Le Bachelier C, Mathieu L, Rotig A, Boneh A. 70.  et al. 2014. Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum. Mol. Genet. 23:2106–19 [Google Scholar]
  71. Hofer A, Noe N, Tischner C, Kladt N, Lellek V. 71.  et al. 2014. Defining the action spectrum of potential PGC-1α activators on a mitochondrial and cellular level in vivo. Hum. Mol. Genet. 23:2400–15 [Google Scholar]
  72. Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW. 72.  et al. 2006. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann. Neurol. 60:223–35 [Google Scholar]
  73. Kossoff EH, Hartman AL. 73.  2012. Ketogenic diets: new advances for metabolism-based therapies. Curr. Opin. Neurol. 25:173–78 [Google Scholar]
  74. Kang HC, Lee YM, Kim HD, Lee JS, Slama A. 74.  2007. Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia 48:82–88 [Google Scholar]
  75. Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM. 75.  2004. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann. Neurol. 55:576–80 [Google Scholar]
  76. Valentino ML, Barboni P, Ghelli A, Bucchi L, Rengo C. 76.  et al. 2004. The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy. Ann. Neurol. 56:631–41 [Google Scholar]
  77. Nakano K, Tarashima M, Tachikawa E, Noda N, Nakayama T. 77.  et al. 2005. Platelet mitochondrial evaluation during cytochrome i and dichloroacetate treatments of MELAS. Mitochondrion 5:426–33 [Google Scholar]
  78. Lattanzi L, Salvatori G, Coletta M, Sonnino C, Cusella De Angelis MG. 78.  et al. 1998. High efficiency myogenic conversion of human fibroblasts by adenoviral vector-mediated MyoD gene transfer. An alternative strategy for ex vivo gene therapy of primary myopathies. J. Clin. Investig. 101:2119–28 [Google Scholar]
  79. Saada A. 79.  2014. Mitochondria: mitochondrial OXPHOS (dys) function ex vivo: the use of primary fibroblasts. Int. J. Biochem. Cell Biol. 48:60–65 [Google Scholar]
  80. Lopez LC, Luna-Sanchez M, Garcia-Corzo L, Quinzii CM, Hirano M. 80.  2014. Pathomechanisms in coenzyme Q10-deficient human fibroblasts. Mol. Syndromol. 5:163–69 [Google Scholar]
  81. Lopez LC, Quinzii CM, Area E, Naini A, Rahman S. 81.  et al. 2010. Treatment of CoQ10 deficient fibroblasts with ubiquinone, CoQ analogs, and vitamin C: time- and compound-dependent effects. PLOS ONE 5:e11897 [Google Scholar]
  82. Bar-Meir M, Elpeleg ON, Saada A. 82.  2001. Effect of various agents on adenosine triphosphate synthesis in mitochondrial complex I deficiency. J. Pediatr. 139:868–70 [Google Scholar]
  83. Jauslin ML, Meier T, Smith RA, Murphy MP. 83.  2003. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J 17:1972–74 [Google Scholar]
  84. Suzuki T, Yamaguchi H, Kikusato M, Matsuhashi T, Matsuo A. 84.  et al. 2015. Mitochonic acid 5 (MA-5), a derivative of the plant hormone indole-3-acetic acid, improves survival of fibroblasts from patients with mitochondrial diseases. Tohoku J. Exp. Med. 236:225–32 [Google Scholar]
  85. King MP, Koga Y, Davidson M, Schon EA. 85.  1992. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu(UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol. Cell. Biol. 12:480–90 [Google Scholar]
  86. Masucci JP, Davidson M, Koga Y, Schon EA, King MP. 86.  1995. In vitro analysis of mutations causing myoclonus epilepsy with ragged-red fibers in the mitochondrial tRNALys gene: Two genotypes produce similar phenotypes. Mol. Cell. Biol. 15:2872–81 [Google Scholar]
  87. Jun AS, Trounce IA, Brown MD, Shoffner JM, Wallace DC. 87.  1996. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. Mol. Cell. Biol. 16:771–77 [Google Scholar]
  88. Ishikawa K, Hayashi J. 88.  2009. Generation of mtDNA-exchanged cybrids for determination of the effects of mtDNA mutations on tumor phenotypes. Methods Enzymol 457:335–46 [Google Scholar]
  89. Petrova-Benedict R, Buncic JR, Wallace DC, Robinson BH. 89.  1992. Selective killing of cells with oxidative defects in galactose medium: a screening test for affected patient fibroblasts. J. Inherit. Metab. Dis. 15:943–44 [Google Scholar]
  90. D'Aurelio M, Pallotti F, Barrientos A, Gajewski CD, Kwong JQ. 90.  et al. 2001. In vivo regulation of oxidative phosphorylation in cells harboring a stop-codon mutation in mitochondrial DNA-encoded cytochrome c oxidase subunit I. J. Biol. Chem. 276:46925–32 [Google Scholar]
  91. Santra S, Gilkerson RW, Davidson M, Schon EA. 91.  2004. Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Ann. Neurol. 56:662–69 [Google Scholar]
  92. Suen DF, Narendra DP, Tanaka A, Manfredi G, Youle RJ. 92.  2010. Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. PNAS 107:11835–40 [Google Scholar]
  93. Desquiret-Dumas V, Gueguen N, Barth M, Chevrollier A, Hancock S. 93.  et al. 2012. Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS. Biochim. Biophys. Acta 1822:1019–29 [Google Scholar]
  94. Sgarbi G, Casalena GA, Baracca A, Lenaz G, DiMauro S, Solaini G. 94.  2009. Human NARP mitochondrial mutation metabolism corrected with α-ketoglutarate/aspartate: a potential new therapy. Arch. Neurol. 66:951–57 [Google Scholar]
  95. Mullen AR, Hu Z, Shi X, Jiang L, Boroughs LK. 95.  et al. 2014. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep 7:1679–90 [Google Scholar]
  96. Garrido-Maraver J, Cordero MD, Monino ID, Pereira-Arenas S, Lechuga-Vieco AV. 96.  et al. 2012. Screening of effective pharmacological treatments for MELAS syndrome using yeasts, fibroblasts and cybrid models of the disease. Br. J. Pharmacol. 167:1311–28 [Google Scholar]
  97. Mattiazzi M, Vijayvergiya C, Gajewski CD, DeVivo DC, Lenaz G. 97.  et al. 2004. The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum. Mol. Genet. 13:869–79 [Google Scholar]
  98. Prigione A, Lichtner B, Kuhl H, Struys EA, Wamelink M. 98.  et al. 2011. Human induced pluripotent stem cells harbor homoplasmic and heteroplasmic mitochondrial DNA mutations while maintaining human embryonic stem cell-like metabolic reprogramming. Stem Cells 29:1338–48 [Google Scholar]
  99. Hamalainen RH, Suomalainen A. 99.  2016. Generation and characterization of induced pluripotent stem cells from patients with mtDNA mutations. Methods Mol. Biol. 1353:65–75 [Google Scholar]
  100. Hatakeyama H, Katayama A, Komaki H, Nishino I, Goto Y. 100.  2015. Molecular pathomechanisms and cell-type-specific disease phenotypes of MELAS caused by mutant mitochondrial tRNATrp. Acta Neuropathol. Commun. 3:52 [Google Scholar]
  101. Hick A, Wattenhofer-Donze M, Chintawar S, Tropel P, Simard JP. 101.  et al. 2013. Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich's ataxia. Dis. Model. Mech. 6:608–21 [Google Scholar]
  102. Folmes CD, Martinez-Fernandez A, Perales-Clemente E, Li X, McDonald A. 102.  et al. 2013. Disease-causing mitochondrial heteroplasmy segregated within induced pluripotent stem cell clones derived from a patient with MELAS. Stem Cells 31:1298–308 [Google Scholar]
  103. Ma H, Folmes CD, Wu J, Morey R, Mora-Castilla S. 103.  et al. 2015. Metabolic rescue in pluripotent cells from patients with mtDNA disease. Nature 524:234–38 [Google Scholar]
  104. Schatz G. 104.  1963. The isolation of possible mitochondrial precursor structures from aerobically grown baker's yeast. Biochem. Biophys. Res. Commun. 12:448–51 [Google Scholar]
  105. Reid GA, Schatz G. 105.  1982. Import of proteins into mitochondria. Extramitochondrial pools and post-translational import of mitochondrial protein precursors in vivo. J. Biol. Chem. 257:13062–67 [Google Scholar]
  106. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB. 106.  et al. 2008. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–23 [Google Scholar]
  107. Baruffini E, Ferrero I, Foury F. 107.  2007. Mitochondrial DNA defects in Saccharomyces cerevisiae caused by functional interactions between DNA polymerase gamma mutations associated with disease in human. Biochim. Biophys. Acta 1772:1225–35 [Google Scholar]
  108. Lasserre JP, Dautant A, Aiyar RS, Kucharczyk R, Glatigny A. 108.  et al. 2015. Yeast as a system for modeling mitochondrial disease mechanisms and discovering therapies. Dis. Model. Mech. 8:509–26 [Google Scholar]
  109. Bulder CJ. 109.  1964. Lethality of the petite mutation in petite negative yeasts. Antonie Van Leeuwenhoek 30:442–54 [Google Scholar]
  110. Dimmer KS, Fritz S, Fuchs F, Messerschmitt M, Weinbach N. 110.  et al. 2002. Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. . Mol. Biol. Cell 13:847–53 [Google Scholar]
  111. Barrientos A. 111.  2003. Yeast models of human mitochondrial diseases. IUBMB Life 55:83–95 [Google Scholar]
  112. Bonnefoy N, Fox TD. 112.  2001. Genetic transformation of Saccharomyces cerevisiae mitochondria. Methods Cell Biol 65:381–96 [Google Scholar]
  113. Claypool SM, Boontheung P, McCaffery JM, Loo JA, Koehler CM. 113.  2008. The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome. Mol. Biol. Cell 19:5143–55 [Google Scholar]
  114. Barrientos A, Korr D, Tzagoloff A. 114.  2002. Shy1p is necessary for full expression of mitochondrial COX1 in the yeast model of Leigh's syndrome. EMBO J 21:43–52 [Google Scholar]
  115. Mashkevich G, Repetto B, Glerum DM, Jin C, Tzagoloff A. 115.  1997. SHY1, the yeast homolog of the mammalian SURF-1 gene, encodes a mitochondrial protein required for respiration. J. Biol. Chem. 272:14356–64 [Google Scholar]
  116. Coppola M, Pizzigoni A, Banfi S, Bassi MT, Casari G, Incerti B. 116.  2000. Identification and characterization of YME1L1, a novel paraplegin-related gene. Genomics 66:48–54 [Google Scholar]
  117. Kerscher SJ. 117.  2000. Diversity and origin of alternative NADH:ubiquinone oxidoreductases. Biochim. Biophys. Acta 1459:274–83 [Google Scholar]
  118. Ogilvie I, Kennaway NG, Shoubridge EA. 118.  2005. A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J. Clin. Investig. 115:2784–92 [Google Scholar]
  119. Schwimmer C, Rak M, Lefebvre-Legendre L, Duvezin-Caubet S, Plane G, di Rago JP. 119.  2006. Yeast models of human mitochondrial diseases: from molecular mechanisms to drug screening. Biotechnol. J. 1:270–81 [Google Scholar]
  120. Cheng WC, Leach KM, Hardwick JM. 120.  2008. Mitochondrial death pathways in yeast and mammalian cells. Biochim. Biophys. Acta 1783:1272–79 [Google Scholar]
  121. Bassett DE Jr., Boguski MS, Hieter P. 121.  1996. Yeast genes and human disease. Nature 379:589–90 [Google Scholar]
  122. Shadel GS, Clayton DA. 122.  1993. Mitochondrial transcription initiation. Variation and conservation. J. Biol. Chem. 268:16083–86 [Google Scholar]
  123. Shadel GS. 123.  1999. Yeast as a model for human mtDNA replication. Am. J. Hum. Genet. 65:1230–37 [Google Scholar]
  124. Rea SL, Graham BH, Nakamaru-Ogiso E, Kar A, Falk MJ. 124.  2010. Bacteria, yeast, worms, and flies: exploiting simple model organisms to investigate human mitochondrial diseases. Dev. Disabil. Res. Rev. 16:200–18 [Google Scholar]
  125. Brenner S. 125.  1974. The genetics of Caenorhabditis elegans. . Genetics 77:71–94 [Google Scholar]
  126. Hartman PS, Ishii N, Kayser EB, Morgan PG, Sedensky MM. 126.  2001. Mitochondrial mutations differentially affect aging, mutability and anesthetic sensitivity in Caenorhabditis elegans. . Mech. Ageing Dev. 122:1187–201 [Google Scholar]
  127. McCormack S, Polyak E, Ostrovsky J, Dingley SD, Rao M. 127.  et al. 2015. Pharmacologic targeting of sirtuin and PPAR signaling improves longevity and mitochondrial physiology in respiratory chain complex I mutant Caenorhabditis elegans. . Mitochondrion 22:45–59 [Google Scholar]
  128. 128. C. elegans Seq. Consort. 1998. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282:2012–18 [Google Scholar]
  129. Sonnhammer EL, Durbin R. 129.  1997. Analysis of protein domain families in Caenorhabditis elegans. . Genomics 46:200–16 [Google Scholar]
  130. Kuwabara PE, O'Neil N. 130.  2001. The use of functional genomics in C. elegans for studying human development and disease. J. Inherit. Metab. Dis. 24:127–38 [Google Scholar]
  131. Maglioni S, Ventura N. 131.  2016. C. elegans as a model organism for human mitochondrial associated disorders. Mitochondrion 30:117–25 [Google Scholar]
  132. Grad LI, Lemire BD. 132.  2006. Riboflavin enhances the assembly of mitochondrial cytochrome c oxidase in C. elegans NADH-ubiquinone oxidoreductase mutants. Biochim. Biophys. Acta 1757:115–22 [Google Scholar]
  133. Sen A, Cox RT. 133.  2017. Fly models of human diseases: Drosophila as a model for understanding human mitochondrial mutations and disease. Curr. Top. Dev. Biol. 121:1–27 [Google Scholar]
  134. Chen Z, Qi Y, French S, Zhang G, Covian Garcia R. 134.  et al. 2015. Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function. Mol. Biol. Cell 26:674–84 [Google Scholar]
  135. Meiklejohn CD, Holmbeck MA, Siddiq MA, Abt DN, Rand DM, Montooth KL. 135.  2013. An Incompatibility between a mitochondrial tRNA and its nuclear-encoded tRNA synthetase compromises development and fitness in Drosophila. . PLOS Genet 9:e1003238 [Google Scholar]
  136. Holmbeck MA, Donner JR, Villa-Cuesta E, Rand DM. 136.  2015. A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase. Dis. Model. Mech. 8:843–54 [Google Scholar]
  137. Anderson PR, Kirby K, Hilliker AJ, Phillips JP. 137.  2005. RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila. . Hum. Mol. Genet. 14:3397–405 [Google Scholar]
  138. Bayat V, Thiffault I, Jaiswal M, Tetreault M, Donti T. 138.  et al. 2012. Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLOS Biol 10:e1001288 [Google Scholar]
  139. Da-Re C, von Stockum S, Biscontin A, Millino C, Cisotto P. 139.  et al. 2014. Leigh syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing. J. Biol. Chem. 289:29235–46 [Google Scholar]
  140. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR. 140.  et al. 2006. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. . Nature 441:1162–66 [Google Scholar]
  141. Park J, Lee SB, Lee S, Kim Y, Song S. 141.  et al. 2006. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. . Nature 441:1157–61 [Google Scholar]
  142. Toivonen JM, O'Dell KM, Petit N, Irvine SC, Knight GK. 142.  et al. 2001. Technical knockout, a Drosophila model of mitochondrial deafness. Genetics 159:241–54 [Google Scholar]
  143. Pesah Y, Pham T, Burgess H, Middlebrooks B, Verstreken P. 143.  et al. 2004. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131:2183–94 [Google Scholar]
  144. Steele SL, Prykhozhij SV, Berman JN. 144.  2014. Zebrafish as a model system for mitochondrial biology and diseases. Transl. Res. 163:79–98 [Google Scholar]
  145. Broughton RE, Milam JE, Roe BA. 145.  2001. The complete sequence of the zebrafish (Danio rerio) mitochondrial genome and evolutionary patterns in vertebrate mitochondrial DNA. Genome Res 11:1958–67 [Google Scholar]
  146. Nasevicius A, Ekker SC. 146.  2000. Effective targeted gene ‘knockdown’ in zebrafish. Nat. Genet. 26:216–20 [Google Scholar]
  147. Sander JD, Cade L, Khayter C, Reyon D, Peterson RT. 147.  et al. 2011. Targeted gene disruption in somatic zebrafish cells using engineered TALENs. Nat. Biotechnol. 29:697–98 [Google Scholar]
  148. Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ. 148.  et al. 2013. Efficient genome editing in zebrafish using a CRISPR-Cas system. Nat. Biotechnol. 31:227–29 [Google Scholar]
  149. Stewart AM, Braubach O, Spitsbergen J, Gerlai R, Kalueff AV. 149.  2014. Zebrafish models for translational neuroscience research: from tank to bedside. Trends Neurosci 37:264–78 [Google Scholar]
  150. Sager JJ, Bai Q, Burton EA. 150.  2010. Transgenic zebrafish models of neurodegenerative diseases. Brain Struct. Funct. 214:285–302 [Google Scholar]
  151. Volkoff H, Peter RE. 151.  2006. Feeding behavior of fish and its control. Zebrafish 3:131–40 [Google Scholar]
  152. Makky K, Duvnjak P, Pramanik K, Ramchandran R, Mayer AN. 152.  2008. A whole-animal microplate assay for metabolic rate using zebrafish. J. Biomol. Screen. 13:960–67 [Google Scholar]
  153. Vempati UD, Torraco A, Moraes CT. 153.  2008. Mouse models of oxidative phosphorylation dysfunction and disease. Methods 46:241–47 [Google Scholar]
  154. Torraco A, Peralta S, Iommarini L, Diaz F. 154.  2015. Mitochondrial diseases part I: mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors. Mitochondrion 21:76–91 [Google Scholar]
  155. Iommarini L, Peralta S, Torraco A, Diaz F. 155.  2015. Mitochondrial diseases part II: mouse models of OXPHOS deficiencies caused by defects in regulatory factors and other components required for mitochondrial function. Mitochondrion 22:96–118 [Google Scholar]
  156. Shadel GS, Clayton DA. 156.  1997. Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66:409–35 [Google Scholar]
  157. Bonawitz ND, Clayton DA, Shadel GS. 157.  2006. Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Mol. Cell 24:813–25 [Google Scholar]
  158. Fisher RP, Clayton DA. 158.  1985. A transcription factor required for promoter recognition by human mitochondrial RNA polymerase. Accurate initiation at the heavy- and light-strand promoters dissected and reconstituted in vitro. J. Biol. Chem. 260:11330–38 [Google Scholar]
  159. Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P. 159.  et al. 1998. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18:231–36 [Google Scholar]
  160. West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM. 160.  et al. 2015. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:553–57 [Google Scholar]
  161. Larsson NG, Rustin P. 161.  2001. Animal models for respiratory chain disease. Trends Mol. Med. 7:578–81 [Google Scholar]
  162. Torraco A, Diaz F, Vempati UD, Moraes CT. 162.  2009. Mouse models of oxidative phosphorylation defects: powerful tools to study the pathobiology of mitochondrial diseases. Biochim. Biophys. Acta 1793:171–80 [Google Scholar]
  163. Li H, Wang J, Wilhelmsson H, Hansson A, Thoren P. 163.  et al. 2000. Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy. PNAS 97:3467–72 [Google Scholar]
  164. Wang J, Wilhelmsson H, Graff C, Li H, Oldfors A. 164.  et al. 1999. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat. Genet. 21:133–37 [Google Scholar]
  165. Hansson A, Hance N, Dufour E, Rantanen A, Hultenby K. 165.  et al. 2004. A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts. PNAS 101:3136–41 [Google Scholar]
  166. Gineste C, Hernandez A, Ivarsson N, Cheng AJ, Naess K. 166.  et al. 2015. Cyclophilin D, a target for counteracting skeletal muscle dysfunction in mitochondrial myopathy. Hum. Mol. Genet. 24:6580–87 [Google Scholar]
  167. McCulloch V, Seidel-Rogol BL, Shadel GS. 167.  2002. A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Mol. Cell. Biol. 22:1116–25 [Google Scholar]
  168. Falkenberg M, Gaspari M, Rantanen A, Trifunovic A, Larsson NG, Gustafsson CM. 168.  2002. Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. Nat. Genet. 31:289–94 [Google Scholar]
  169. Cotney J, McKay SE, Shadel GS. 169.  2009. Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness. Hum. Mol. Genet. 18:2670–82 [Google Scholar]
  170. Metodiev MD, Lesko N, Park CB, Camara Y, Shi Y. 170.  et al. 2009. Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome. Cell Metab 9:386–97 [Google Scholar]
  171. McKay SE, Yan W, Nouws J, Thormann MJ, Raimundo N. 171.  et al. 2015. Auditory pathology in a transgenic mtTFB1 mouse model of mitochondrial deafness. Am. J. Pathol. 185:3132–40 [Google Scholar]
  172. Raimundo N, Song L, Shutt TE, McKay SE, Cotney J. 172.  et al. 2012. Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell 148:716–26 [Google Scholar]
  173. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT. 173.  et al. 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429:417–23 [Google Scholar]
  174. Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS. 174.  et al. 2008. DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat. Genet. 40:392–94 [Google Scholar]
  175. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K. 175.  et al. 2005. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–84 [Google Scholar]
  176. Saleem A, Safdar A, Kitaoka Y, Ma X, Marquez OS. 176.  et al. 2015. Polymerase gamma mutator mice rely on increased glycolytic flux for energy production. Mitochondrion 21:19–26 [Google Scholar]
  177. Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS. 177.  et al. 2007. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat. Genet. 39:540–43 [Google Scholar]
  178. Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ. 178.  et al. 2010. Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9:536–44 [Google Scholar]
  179. Hamalainen RH, Ahlqvist KJ, Ellonen P, Lepisto M, Logan A. 179.  et al. 2015. mtDNA mutagenesis disrupts pluripotent stem cell function by altering redox signaling. Cell Rep 11:1614–24 [Google Scholar]
  180. Shabalina IG, Vyssokikh MY, Gibanova N, Csikasz RI, Edgar D. 180.  et al. 2017. Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging 9:315–39 [Google Scholar]
  181. Safdar A, Bourgeois JM, Ogborn DI, Little JP, Hettinga BP. 181.  et al. 2011. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. PNAS 108:4135–40 [Google Scholar]
  182. Yadak R, Sillevis Smitt P, van Gisbergen MW, van Til NP, de Coo IF. 182.  2017. Mitochondrial neurogastrointestinal encephalomyopathy caused by thymidine phosphorylase enzyme deficiency: from pathogenesis to emerging therapeutic options. Front. Cell Neurosci. 11:31 [Google Scholar]
  183. Haraguchi M, Tsujimoto H, Fukushima M, Higuchi I, Kuribayashi H. 183.  et al. 2002. Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice. Mol. Cell. Biol. 22:5212–21 [Google Scholar]
  184. Lopez LC, Akman HO, Garcia-Cazorla A, Dorado B, Marti R. 184.  et al. 2009. Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice. Hum. Mol. Genet. 18:714–22 [Google Scholar]
  185. Marchington DR, Barlow D, Poulton J. 185.  1999. Transmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: developing the first mouse model of mitochondrial DNA disease. Nat. Med. 5:957–60 [Google Scholar]
  186. Sligh JE, Levy SE, Waymire KG, Allard P, Dillehay DL. 186.  et al. 2000. Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. PNAS 97:14461–66 [Google Scholar]
  187. Fan W, Waymire KG, Narula N, Li P, Rocher C. 187.  et al. 2008. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319:958–62 [Google Scholar]
  188. Yokota M, Shitara H, Hashizume O, Ishikawa K, Nakada K. 188.  et al. 2010. Generation of trans-mitochondrial mito-mice by the introduction of a pathogenic G13997A mtDNA from highly metastatic lung carcinoma cells. FEBS Lett 584:3943–48 [Google Scholar]
  189. Shimizu A, Mito T, Hayashi C, Ogasawara E, Koba R. 189.  et al. 2014. Transmitochondrial mice as models for primary prevention of diseases caused by mutation in the tRNALys gene. PNAS 111:3104–9 [Google Scholar]
  190. Inoue K, Nakada K, Ogura A, Isobe K, Goto Y. 190.  et al. 2000. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat. Genet. 26:176–81 [Google Scholar]
  191. Nakada K, Sato A, Sone H, Kasahara A, Ikeda K. 191.  et al. 2004. Accumulation of pathogenic ΔmtDNA induced deafness but not diabetic phenotypes in mito-mice. Biochem. Biophys. Res. Commun. 323:175–84 [Google Scholar]
  192. Levy SE, Waymire KG, Kim YL, MacGregor GR, Wallace DC. 192.  1999. Transfer of chloramphenicol-resistant mitochondrial DNA into the chimeric mouse. Transgenic Res 8:137–45 [Google Scholar]
  193. Kasahara A, Ishikawa K, Yamaoka M, Ito M, Watanabe N. 193.  et al. 2006. Generation of trans-mitochondrial mice carrying homoplasmic mtDNAs with a missense mutation in a structural gene using ES cells. Hum. Mol. Genet. 15:871–81 [Google Scholar]
  194. Shimizu A, Mito T, Hashizume O, Yonekawa H, Ishikawa K. 194.  et al. 2015. G7731A mutation in mouse mitochondrial tRNALys regulates late-onset disorders in transmitochondrial mice. Biochem. Biophys. Res. Commun. 459:66–70 [Google Scholar]
  195. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. 195.  2010. Mitochondrial DNA mutations and human disease. Biochim. Biophys. Acta 1797:113–28 [Google Scholar]
  196. Sato A, Kono T, Nakada K, Ishikawa K, Inoue S. 196.  et al. 2005. Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. PNAS 102:16765–70 [Google Scholar]
  197. Yamanashi H, Hashizume O, Yonekawa H, Nakada K, Hayashi J. 197.  2014. Administration of an antioxidant prevents lymphoma development in transmitochondrial mice overproducing reactive oxygen species. Exp. Anim. 63:459–66 [Google Scholar]
  198. Pinkert CA, Trounce IA. 198.  2002. Production of transmitochondrial mice. Methods 26:348–57 [Google Scholar]
  199. Kauppila JH, Baines HL, Bratic A, Simard ML, Freyer C. 199.  et al. 2016. A phenotype-driven approach to generate mouse models with pathogenic mtDNA mutations causing mitochondrial disease. Cell Rep 16:2980–90 [Google Scholar]
  200. Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M. 200.  et al. 2000. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289:782–85 [Google Scholar]
  201. Longley MJ, Clark S, Yu Wai Man C, Hudson G, Durham SE. 201.  et al. 2006. Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Am. J. Hum. Genet. 78:1026–34 [Google Scholar]
  202. Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP. 202.  et al. 2001. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat. Genet. 28:223–31 [Google Scholar]
  203. Tyynismaa H, Suomalainen A. 203.  2009. Mouse models of mitochondrial DNA defects and their relevance for human disease. EMBO Rep 10:137–43 [Google Scholar]
  204. Tyynismaa H, Mjosund KP, Wanrooij S, Lappalainen I, Ylikallio E. 204.  et al. 2005. Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. PNAS 102:17687–92 [Google Scholar]
  205. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkila S, Wenz T. 205.  et al. 2010. Mitochondrial myopathy induces a starvation-like response. Hum. Mol. Genet. 19:3948–58 [Google Scholar]
  206. Davis RL, Liang C, Edema-Hildebrand F, Riley C, Needham M, Sue CM. 206.  2013. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology 81:1819–26 [Google Scholar]
  207. Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K. 207.  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]
  208. Lehtonen J, Forsstrom S, Viscomi C, Zeviani M, Moraes CT. 208.  et al. 2015. Mitochondrial myopathy biomarker Fibroblast growth factor 21 is induced by muscle mtDNA instability and translation defects. Mitochondrion 24:S45–46 [Google Scholar]
  209. Nikkanen J, Forsstrom S, Euro L, Paetau I, Kohnz RA. 209.  et al. 2016. Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism. Cell Metab 23:635–48 [Google Scholar]
  210. Ahola-Erkkila S, Carroll CJ, Peltola-Mjosund K, Tulkki V, Mattila I. 210.  et al. 2010. Ketogenic diet slows down mitochondrial myopathy progression in mice. Hum. Mol. Genet. 19:1974–84 [Google Scholar]
  211. Ahola-Erkkila S, Auranen M, Isohanni P, Lundbom N, Piirila P. 211.  et al. 2013. Pilot study: modified Aktins diet trial for adult-onset mitochondrial myopathy. Mitochondrion 13:911 [Google Scholar]
  212. Budde SM, van den Heuvel LP, Smeets RJ, Skladal D, Mayr JA. 212.  et al. 2003. Clinical heterogeneity in patients with mutations in the NDUFS4 gene of mitochondrial complex I. J. Inherit. Metab. Dis. 26:813–15 [Google Scholar]
  213. Petruzzella V, Vergari R, Puzziferri I, Boffoli D, Lamantea E. 213.  et al. 2001. A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome. Hum. Mol. Genet. 10:529–35 [Google Scholar]
  214. Ugalde C, Janssen RJ, van den Heuvel LP, Smeitink JA, Nijtmans LG. 214.  2004. Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency. Hum. Mol. Genet. 13:659–67 [Google Scholar]
  215. Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. 215.  2008. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab 7:312–20 [Google Scholar]
  216. Quintana A, Kruse SE, Kapur RP, Sanz E, Palmiter RD. 216.  2010. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome. PNAS 107:10996–1001 [Google Scholar]
  217. Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M. 217.  et al. 2013. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342:1524–28 [Google Scholar]
  218. McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M. 218.  2011. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 52:e7–11 [Google Scholar]
  219. Ingraham CA, Burwell LS, Skalska J, Brookes PS, Howell RL. 219.  et al. 2009. NDUFS4: creation of a mouse model mimicking a Complex I disorder. Mitochondrion 9:204–10 [Google Scholar]
  220. Quinzii CM, Hirano M, DiMauro S. 220.  2007. CoQ10 deficiency diseases in adults. Mitochondrion 7:Suppl.S122–26 [Google Scholar]
  221. Lopez LC, Schuelke M, Quinzii CM, Kanki T, Rodenburg RJ. 221.  et al. 2006. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am. J. Hum. Genet. 79:1125–29 [Google Scholar]
  222. Quinzii CM, Garone C, Emmanuele V, Tadesse S, Krishna S. 222.  et al. 2013. Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice. FASEB J 27:612–21 [Google Scholar]
  223. Peng M, Falk MJ, Haase VH, King R, Polyak E. 223.  et al. 2008. Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLOS Genet 4:e1000061 [Google Scholar]
  224. Falk MJ, Polyak E, Zhang Z, Peng M, King R. 224.  et al. 2011. Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice. EMBO Mol. Med. 3:410–27 [Google Scholar]
  225. Saiki R, Lunceford AL, Shi Y, Marbois B, King R. 225.  et al. 2008. Coenzyme Q10 supplementation rescues renal disease in Pdss2kd/kd mice with mutations in prenyl diphosphate synthase subunit 2. Am. J. Physiol. Renal. Physiol. 295:F1535–44 [Google Scholar]
  226. Ades LC, Gedeon AK, Wilson MJ, Latham M, Partington MW. 226.  et al. 1993. Barth syndrome: clinical features and confirmation of gene localisation to distal Xq28. Am. J. Med. Genet. 45:327–34 [Google Scholar]
  227. Vreken P, Valianpour F, Nijtmans LG, Grivell LA, Plecko B. 227.  et al. 2000. Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome. Biochem. Biophys. Res. Commun. 279:378–82 [Google Scholar]
  228. Soustek MS, Falk DJ, Mah CS, Toth MJ, Schlame M. 228.  et al. 2011. Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency. Hum. Gene Ther. 22:865–71 [Google Scholar]
  229. Acehan D, Vaz F, Houtkooper RH, James J, Moore V. 229.  et al. 2011. Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome. J. Biol. Chem. 286:899–908 [Google Scholar]
  230. Kiebish MA, Yang K, Liu X, Mancuso DJ, Guan S. 230.  et al. 2013. Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome. J. Lipid Res. 54:1312–25 [Google Scholar]
  231. Ferreira C, Thompson R, Vernon H. 231.  2014. Barth syndrome. GeneReviews RA Pagon, MP Adam, HH Ardinger, SE Wallace, A Amemiya et al. Seattle: Univ. Washington https://www.ncbi.nlm.nih.gov/books/NBK247162/ [Google Scholar]
  232. Phoon CK, Acehan D, Schlame M, Stokes DL, Edelman-Novemsky I. 232.  et al. 2012. Tafazzin knockdown in mice leads to a developmental cardiomyopathy with early diastolic dysfunction preceding myocardial noncompaction. J. Am. Heart Assoc. 1:e000455 [Google Scholar]
  233. Huang Y, Powers C, Madala SK, Greis KD, Haffey WD. 233.  et al. 2015. Cardiac metabolic pathways affected in the mouse model of Barth syndrome. PLOS ONE 10:e0128561 [Google Scholar]
  234. Powers C, Huang Y, Strauss A, Khuchua Z. 234.  2013. Diminished exercise capacity and mitochondrial bc1 complex deficiency in tafazzin-knockdown mice. Front. Physiol. 4:74 [Google Scholar]
  235. Soustek MS, Baligand C, Falk DJ, Walter GA, Lewin AS, Byrne BJ. 235.  2015. Endurance training ameliorates complex 3 deficiency in a mouse model of Barth syndrome. J. Inherit. Metab. Dis. 38:915–22 [Google Scholar]
  236. Kaese S, Verheule S. 236.  2012. Cardiac electrophysiology in mice: a matter of size. Front Physiol 3:345 [Google Scholar]
  237. Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG. 237.  et al. 2015. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep 10:1681–91 [Google Scholar]
  238. Zhang Z, Tsukikawa M, Peng M, Polyak E, Nakamaru-Ogiso E. 238.  et al. 2013. Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network. PLOS ONE 8:e69282 [Google Scholar]
  239. Felici R, Lapucci A, Cavone L, Pratesi S, Berlinguer-Palmini R, Chiarugi A. 239.  2015. Pharmacological NAD-boosting strategies improve mitochondrial homeostasis in human complex I–mutant fibroblasts. Mol. Pharmacol. 87:965–71 [Google Scholar]
  240. Verkaart S, Koopman WJ, Cheek J, van Emst-de Vries SE, van den Heuvel LW. 240.  et al. 2007. Mitochondrial and cytosolic thiol redox state are not detectably altered in isolated human NADH:ubiquinone oxidoreductase deficiency. Biochim. Biophys. Acta 1772:1041–51 [Google Scholar]
  241. Valsecchi F, Monge C, Forkink M, de Groof AJ, Benard G. 241.  et al. 2012. Metabolic consequences of NDUFS4 gene deletion in immortalized mouse embryonic fibroblasts. Biochim. Biophys. Acta 1817:1925–36 [Google Scholar]
  242. Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz SC Jr., Suthammarak W. 242.  et al. 2013. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab 18:239–50 [Google Scholar]
  243. Khan NA, Auranen M, Paetau I, Pirinen E, Euro L. 243.  et al. 2014. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol. Med. 6:721–31 [Google Scholar]

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error