Register      Login



Volume / Issue

Online First

Related articles

VOLUME 1 , ISSUE 1 ( January-March, 2022 ) > List of Articles


Development and Functions of Mitochondria in Early Life

Jinghua Peng, Balamurugan Ramatchandirin, Alexia Pearah, Akhil Maheshwari, Ling He

Keywords : Early life, Metabolism, Mitochondria, Mitochondrial dynamics, Neonatal development, Oocyte maturation

Citation Information : Peng J, Ramatchandirin B, Pearah A, Maheshwari A, He L. Development and Functions of Mitochondria in Early Life. 2022; 1 (1):131-141.

DOI: 10.5005/jp-journals-11002-0013

License: CC BY-NC 4.0

Published Online: 31-03-2022

Copyright Statement:  Copyright © 2022; The Author(s).


Mitochondria are highly dynamic organelles of bacterial origin in eukaryotic cells. These play a central role in metabolism and adenosine triphosphate (ATP) synthesis and in the production and regulation of reactive oxygen species (ROS). In addition to the generation of energy, mitochondria perform numerous other functions to support key developmental events such as fertilization during reproduction, oocyte maturation, and the development of the embryo. During embryonic and neonatal development, mitochondria may have important effects on metabolic, energetic, and epigenetic regulation, which may have significant short- and long-term effects on embryonic and offspring health. Hence, the environment, epigenome, and early-life regulation are all linked by mitochondrial integrity, communication, and metabolism.

  1. Souid AK, Penefsky HS. Mechanism of ATP synthesis by mitochondrial ATP synthase from beef heart. J Bioenergetics Biomembranes 1994;26(6):627–630. DOI: 10.1007/BF00831537.
  2. Wallace DC. Mitochondrial diseases in man and mouse. Science 1999;283(5407):1482–1488. DOI: 10.1126/science.283.5407.1482.
  3. Lopez J, Tait SW. Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer 2015;112(6):957–962. DOI: 10.1038/bjc.2015.85.
  4. Munro D, Treberg JR. A radical shift in perspective: mitochondria as regulators of reactive oxygen species. J Exp Biol 2017;220 (Pt 7):1170–1180. DOI: 10.1242/jeb.132142.
  5. Bohovych I, Khalimonchuk O. Sending out an SOS: mitochondria as a signaling hub. Front Cell Dev Biol 2016;4:109. DOI: 10.3389/fcell.2016.00109.
  6. Hill S, Van Remmen H. Mitochondrial stress signaling in longevity: a new role for mitochondrial function in aging. Redox Biol 2014;2: 936–944. DOI: 10.1016/j.redox.2014.07.005.
  7. Sathananthan AH, Trounson AO. Mitochondrial morphology during preimplantational human embryogenesis. Hum Reprod 2000;15 Suppl 2:148–159. DOI: 10.1093/humrep/15.suppl_2.148.
  8. Motta PM, Nottola SA, Makabe S, et al. Mitochondrial morphology in human fetal and adult female germ cells. Hum Reprod 2000;15 Suppl 2:129–147. DOI: 10.1093/humrep/15.suppl_2.129.
  9. Lai L, Leone TC, Zechner C, et al. Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev 2008;22(14):1948–1961. DOI: 10.1101/gad.1661708.
  10. El-Merhie N, Baumgart-Vogt E, Pilatz A, et al. Differential alterations of the mitochondrial morphology and respiratory chain complexes during postnatal development of the mouse lung. Oxid Med Cell Longev 2017;2017:9169146. DOI: 10.1155/2017/9169146.
  11. Sutton R, Pollak JK. Hormone-initiated maturation of rat liver mitochondria after birth. Biochem J 1980;186(1):361–367. DOI: 10.1042/bj1860361.
  12. Bastin J, Delaval E, Freund N, et al. Effects of birth on energy metabolism in the rat kidney. Biochem J 1988;252(2):337–341. DOI: 10.1042/bj2520337.
  13. Yang D, Oyaizu Y, Oyaizu H, et al. Mitochondrial origins. Proc Natl Acad Sci USA 1985;82(13):4443–4447. DOI: 10.1073/pnas.82.13.4443.
  14. Roger AJ, Munoz-Gomez SA, Kamikawa R. The origin and diversification of mitochondria. Curr Biol 2017;27(21):R1177–R1192. DOI: 10.1016/j.cub.2017.09.015.
  15. Martin WF, Garg S, Zimorski V. Endosymbiotic theories for eukaryote origin. Philos Trans R Soc Lond B Biol Sci 2015;370(1678):20140330. DOI: 10.1098/rstb.2014.0330.
  16. Lopez-Garcia P, Moreira D. Open questions on the origin of eukaryotes. Trends Ecol Evol 2015;30(11):697–708. DOI: 10.1016/j.tree.2015.09.005.
  17. Calvo SE, Mootha VK. The mitochondrial proteome and human disease. Annu Rev Genomics Hum Genet 2010;11:25–44. DOI: 10.1146/annurev-genom-082509-141720.
  18. Pfanner N, Warscheid B, Wiedemann N. Mitochondrial proteins: from biogenesis to functional networks. Nat Rev Mol Cell Biol 2019;20(5):267–284. DOI: 10.1038/s41580-018-0092-0.
  19. Boengler K, Heusch G, Schulz R. Nuclear-encoded mitochondrial proteins and their role in cardioprotection. Biochim Biophys Acta 2011;1813(7):1286–1294. DOI: 10.1016/j.bbamcr.2011.01.009.
  20. Harris DA, Das AM. Control of mitochondrial ATP synthesis in the heart. Biochem J 1991;280(Pt 3):561–573. DOI: 10.1042/bj2800561.
  21. Harvey AJ. Mitochondria in early development: linking the microenvironment, metabolism and the epigenome. Reproduction 2019;157(5):R159–R179. DOI: 10.1530/REP-18-0431.
  22. Giles RE, Blanc H, Cann HM, et al. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A 1980;77(11):6715–6719. DOI: 10.1073/pnas.77.11.6715.
  23. Artuso L, Romano A, Verri T, et al. Mitochondrial DNA metabolism in early development of zebrafish (Danio rerio). Biochim Biophys Acta 2012;1817(7):1002–1011. DOI: 10.1016/j.bbabio.2012.03.019.
  24. Dumesic DA, Meldrum DR, Katz-Jaffe MG, et al. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril 2015;103(2):303–316. DOI: 10.1016/j.fertnstert.2014.11.015.
  25. Houghton FD, Thompson JG, Kennedy CJ, et al. Oxygen consumption and energy metabolism of the early mouse embryo. Mol Reprod Dev 1996;44(4):476–485. DOI: 10.1002/(SICI)1098-2795(199608)44:4<476::AID-MRD7>3.0.CO;2-I.
  26. Gardner DK, Wale PL. Analysis of metabolism to select viable human embryos for transfer. Fertil Steril 2013;99(4):1062–1072. DOI: 10.1016/j.fertnstert.2012.12.004.
  27. May-Panloup P, Chretien MF, Jacques C, et al. Low oocyte mitochondrial DNA content in ovarian insufficiency. Hum Reprod 2005;20(3):593–597. DOI: 10.1093/humrep/deh667.
  28. Santos TA, El Shourbagy S, St John JC. Mitochondrial content reflects oocyte variability and fertilization outcome. Fertil Steril 2006;85(3):584–591. DOI: 10.1016/j.fertnstert.2005.09.017.
  29. Reynier P, May-Panloup P, Chretien MF, et al. Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod 2001;7(5):425–429. DOI: 10.1093/molehr/7.5.425.
  30. Murakoshi Y, Sueoka K, Takahashi K, et al. Embryo developmental capability and pregnancy outcome are related to the mitochondrial DNA copy number and ooplasmic volume. J Assist Reprod Genet 2013;30(10):1367–1375. DOI: 10.1007/s10815-013-0062-6.
  31. Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004;429(6990):417–423. DOI: 10.1038/nature02517.
  32. Ge H, Tollner TL, Hu Z, et al. The importance of mitochondrial metabolic activity and mitochondrial DNA replication during oocyte maturation in vitro on oocyte quality and subsequent embryo developmental competence. Mol Reprod Dev 2012;79(6):392–401. DOI: 10.1002/mrd.22042.
  33. Van Blerkom J, Davis PW, Lee J. ATP content of human oocytes and developmental potential and outcome after in vitro fertilization and embryo transfer. Hum Reprod 1995;10(2):415–424. DOI: 10.1093/oxfordjournals.humrep.a135954.
  34. Wakefield SL, Lane M, Mitchell M. Impaired mitochondrial function in the preimplantation embryo perturbs fetal and placental development in the mouse. Biol Reprod 2011;84(3):572–580. DOI: 10.1095/biolreprod.110.087262.
  35. Mandal S, Lindgren AG, Srivastava AS, et al. Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells 2011;29(3):486–495. DOI: 10.1002/stem.590.
  36. Duchen MR. Mitochondria and calcium: from cell signalling to cell death. J Physiol 2000;529 Pt 1:57–68. DOI: 10.1111/j.1469-7793.2000.00057.x.
  37. Kline D, Kline JT. Repetitive calcium transients and the role of calcium in exocytosis and cell cycle activation in the mouse egg. Dev Biol 1992;149(1):80–89. DOI: 10.1016/0012-1606(92)90265-i.
  38. Stricker SA. Comparative biology of calcium signaling during fertilization and egg activation in animals. Dev Biol 1999;211(2): 157–176. DOI: 10.1006/dbio.1999.9340.
  39. Dumollard R, Marangos P, Fitzharris G, et al. Sperm-triggered [Ca2+] oscillations and Ca2+ homeostasis in the mouse egg have an absolute requirement for mitochondrial ATP production. Development 2004;131(13):3057–3067. DOI: 10.1242/dev.01181.
  40. Young SL, Fram EK, Spain CL, et al. Development of type II pneumocytes in rat lung. Am J Physiol 1991;260(2 Pt 1):L113–L122. DOI: 10.1152/ajplung.1991.260.2.L113.
  41. Plopper CG, Alley JL, Serabjitsingh CJ, et al. Cytodifferentiation of the nonciliated bronchiolar epithelial (Clara) cell during rabbit lung maturation: an ultrastructural and morphometric study. Am J Anat 1983;167(3):329–357. DOI: 10.1002/aja.1001670305.
  42. Valcarce C, Navarrete RM, Encabo P, et al. Postnatal development of rat liver mitochondrial functions. The roles of protein synthesis and of adenine nucleotides. J Biol Chem 1988;263(16):7767–7775. PMID: 2897364.
  43. Izquierdo JM, Luis AM, Cuezva JM. Postnatal mitochondrial differentiation in rat liver. Regulation by thyroid hormones of the beta-subunit of the mitochondrial F1-ATPase complex. J Biol Chem 1990;265(16):9090–9097. PMID: 2140569.
  44. Mayer W, Niveleau A, Walter J, et al. Demethylation of the zygotic paternal genome. Nature 2000;403(6769):501–502. DOI: 10.1038/35000656.
  45. Lozoya OA, Martinez-Reyes I, Wang T, et al. Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation. PLoS Biol 2018;16(4):e2005707. DOI: 10.1371/journal.pbio.2005707.
  46. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem 1990;1(5):228–237. DOI: 10.1016/0955-2863(90)90070-2.
  47. Sun H, Kang J, Su J, et al. Methionine adenosyltransferase 2A regulates mouse zygotic genome activation and morula to blastocyst transitiondagger. Biol Reprod 2019;100(3):601–617. DOI: 10.1093/biolre/ioy194.
  48. Shojaei Saadi HA, Gagne D, Fournier E, et al. Responses of bovine early embryos to S-adenosyl methionine supplementation in culture. Epigenomics 2016;8(8):1039–1060. DOI: 10.2217/epi- 2016-0022.
  49. Shiraki N, Shiraki Y, Tsuyama T, et al. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab 2014;19(5):780–794. DOI: 10.1016/j.cmet.2014.03.017.
  50. Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 2006;439(7078):811–816. DOI: 10.1038/nature04433.
  51. Canovas S, Cibelli JB, Ross PJ. Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development. Proc Natl Acad Sci U S A 2012;109(7): 2400–2405. DOI: 10.1073/pnas.1119112109.
  52. Carey BW, Finley LW, Cross JR, et al. Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 2015;518(7539):413–416. DOI: 10.1038/nature13981.
  53. Jacob S, Moley KH. Gametes and embryo epigenetic reprogramming affect developmental outcome: implication for assisted reproductive technologies. Pediatr Res 2005;58(3):437–446. DOI: 10.1203/01.PDR.0000179401.17161.D3.
  54. Wellen KE, Hatzivassiliou G, Sachdeva UM, et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009;324(5930):1076–1080. DOI: 10.1126/science.1164097.
  55. Moussaieff A, Rouleau M, Kitsberg D, et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 2015;21(3): 392–402. DOI: 10.1016/j.cmet.2015.02.002.
  56. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13(4):225–238. DOI: 10.1038/nrm3293.
  57. Kawamura Y, Uchijima Y, Horike N, et al. Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest. J Clin Invest 2010;120(8):2817–2828. DOI: 10.1172/JCI42020.
  58. Mitchell M, Cashman KS, Gardner DK, et al. Disruption of mitochondrial malate-aspartate shuttle activity in mouse blastocysts impairs viability and fetal growth. Biol Reprod 2009;80(2):295–301. DOI: 10.1095/biolreprod.108.069864.
  59. Simsek-Duran F, Li F, Ford W, et al. Age-associated metabolic and morphologic changes in mitochondria of individual mouse and hamster oocytes. PLoS One 2013;8(5):e64955. DOI: 10.1371/journal.pone.0064955.
  60. Rebolledo-Jaramillo B, Su MS, Stoler N, et al. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A 2014;111(43):15474–15479. DOI: 10.1073/pnas.1409328111.
  61. Chappel S. The role of mitochondria from mature oocyte to viable blastocyst. Obstet Gynecol Int 2013;2013:183024. DOI: 10.1155/2013/183024.
  62. Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clin Pediatr (Phila) 2003;42(8):703–710. DOI: 10.1177/000992280304200806.
  63. Honzik T, Tesarova M, Mayr JA, et al. Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation. Arch Dis Child 2010;95(4):296–301. DOI: 10.1136/adc.2009.168096.
  64. Gibson K, Halliday JL, Kirby DM, et al. Mitochondrial oxidative phosphorylation disorders presenting in neonates: clinical manifestations and enzymatic and molecular diagnoses. Pediatrics 2008;122(5):1003–1008. DOI: 10.1542/peds.2007-3502.
  65. Spinazzola A. Mitochondrial DNA mutations and depletion in pediatric medicine. Semin Fetal Neonatal Med 2011;16(4):190–196. DOI: 10.1016/j.siny.2011.04.011.
  66. Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders - a step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol Basis Dis 2017;1863(5):1066–1077. DOI: 10.1016/j.bbadis.2016.11.010.
  67. Debray FG, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007;119(4):722–733. DOI: 10.1542/peds.2006-1866.
  68. Sue CM, Hirano M, DiMauro S, et al. Neonatal presentations of mitochondrial metabolic disorders. Semin Perinatol 1999;23(2):113–124. DOI: 10.1016/s0146-0005(99)80045-7.
  69. Danhelovska T, Kolarova H, Zeman J, et al. Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I. BMC Pediatr 2020;20(1):41. DOI: 10.1186/s12887-020-1912-x.
  70. Jackson CB, Nuoffer JM, Hahn D, et al. Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. J Med Genet 2014;51(3):170–175. DOI: 10.1136/jmedgenet-2013-101932.
  71. Ma YY, Wu TF, Liu YP, et al. Two compound frame-shift mutations in succinate dehydrogenase gene of a Chinese boy with encephalopathy. Brain Dev 2014;36(5):394–398. DOI: 10.1016/j.braindev.2013.06.003.
  72. Ghezzi D, Goffrini P, Uziel G, et al. SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet 2009;41(6):654–656. DOI: 10.1038/ng.378.
  73. DiMauro S, Tanji K, Schon EA. The many clinical faces of cytochrome c oxidase deficiency. Adv Exp Med Biol 2012;748:341–357. DOI: 10.1007/978-1-4614-3573-0_14.
  74. Soto IC, Fontanesi F, Liu J, et al. Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core. Biochim Biophys Acta 2012;1817(6):883–897. DOI: 10.1016/j.bbabio.2011.09.005.
  75. Jonckheere AI, Renkema GH, Bras M, et al. A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy. Brain 2013;136(Pt 5):1544–1554. DOI: 10.1093/brain/awt086.
  76. DiMauro S, De Vivo DC. Genetic heterogeneity in Leigh syndrome. Ann Neurol 1996;40(1):5–7. DOI: 10.1002/ana.410400104.
  77. Hayakawa K, Esposito E, Wang X, et al. Corrigendum: transfer of mitochondria from astrocytes to neurons after stroke. Nature 2016;539(7627):123. DOI: 10.1038/nature19805.
  78. Tan AS, Baty JW, Dong LF, et al. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab 2015;21(1):81–94. DOI: 10.1016/j.cmet.2014.12.003.
  79. Rustom A, Saffrich R, Markovic I, et al. Nanotubular highways for intercellular organelle transport. Science 2004;303(5660):1007–1010. DOI: 10.1126/science.1093133.
  80. Sansone P, Savini C, Kurelac I, et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc Natl Acad Sci U S A 2017;114(43):E9066–E9075. DOI: 10.1073/pnas.1704862114.
  81. Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012;18(5):759–765. DOI: 10.1038/nm.2736.
  82. Calabuig-Navarro V, Puchowicz M, Glazebrook P, et al. Effect of omega-3 supplementation on placental lipid metabolism in overweight and obese women. Am J Clin Nutr 2016;103(4):1064–1072. DOI: 10.3945/ajcn.115.124651.
  83. Bale G, Mitra S, de Roever I, et al. Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury. J Cereb Blood Flow Metab 2019;39(10):2035–2047. DOI: 10.1177/0271678X18777928.
  84. Ngo HB, Lovely GA, Phillips R, et al. Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nat Commun 2014;5(1):3077. DOI: 10.1038/ncomms4077.
  85. Gleyzer N, Vercauteren K, Scarpulla RC. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol 2005;25(4):1354–1366. DOI: 10.1128/MCB.25.4.1354-1366.2005.
  86. Yu J, Nagasu H, Murakami T, et al. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci U S A 2014;111(43):15514–15519. DOI: 10.1073/pnas.1414859111.
  87. McIlroy DJ, Jarnicki AG, Au GG, et al. Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery. J Crit Care 2014;29(6):1133.e1–1133.e5. DOI: 10.1016/j.jcrc.2014.07.013.
  88. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science 2004;303(5663):1532–1535. DOI: 10.1126/science.1092385.
  89. Caielli S, Athale S, Domic B, et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med 2016;213(5):697–713. DOI: 10.1084/jem.20151876.
  90. Riley JS, Tait SW. Mitochondrial DNA in inflammation and immunity. EMBO Rep 2020;21(4):e49799. DOI: 10.15252/embr.201949799.
  91. Lunnon K, Ibrahim Z, Proitsi P, et al. Mitochondrial dysfunction and immune activation are detectable in early Alzheimer's disease blood. J Alzheimers Dis 2012;30(3):685–710. DOI: 10.3233/JAD- 2012-111592.
  92. Samavati L, Lee I, Mathes I, et al. Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem 2008;283(30):21134–21144. DOI: 10.1074/jbc.M801954200.
  93. Prajapati P, Sripada L, Singh K, et al. TNF-alpha regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells. Biochim Biophys Acta 2015;1852(3):451–461. DOI: 10.1016/j.bbadis.2014.11.019.
  94. Tang K, Wagner PD, Breen EC. TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure. J Cell Physiol 2010;222(2):320–327. DOI: 10.1002/jcp. 21955.
  95. Palomer X, Alvarez-Guardia D, Rodriguez-Calvo R, et al. TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model. Cardiovasc Res 2009;81(4):703–712. DOI: 10.1093/cvr/cvn327.
  96. van Horssen J, van Schaik P, Witte M. Inflammation and mitochondrial dysfunction: a vicious circle in neurodegenerative disorders? Neurosci Lett 2019;710:132931. DOI: 10.1016/j.neulet.2017.06.050.
  97. Motori E, Puyal J, Toni N, et al. Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab 2013;18(6):844–859. DOI: 10.1016/j.cmet.2013.11.005.
  98. Anusree SS, Nisha VM, Priyanka A, et al. Insulin resistance by TNF-alpha is associated with mitochondrial dysfunction in 3T3-L1 adipocytes and is ameliorated by punicic acid, a PPARgamma agonist. Mol Cell Endocrinol 2015;413:120–128. DOI: 10.1016/j.mce.2015.06.018.
  99. Hahn WS, Kuzmicic J, Burrill JS, et al. Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Am J Physiol Endocrinol Metab 2014;306(9):E1033–E1045. DOI: 10.1152/ajpendo.00422.2013.
  100. Wang Z, Jiang H, Chen S, et al. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 2012;148(1–2):228–243. DOI: 10.1016/j.cell.2011. 11.030.
  101. Ofengeim D, Ito Y, Najafov A, et al. Activation of necroptosis in multiple sclerosis. Cell Rep 2015;10(11):1836–1849. DOI: 10.1016/j.celrep.2015.02.051.
  102. Lees JG, Gardner DK, Harvey AJ. Pluripotent stem cell metabolism and mitochondria: beyond ATP. Stem Cells Int 2017;2017:2874283. DOI: 10.1155/2017/2874283.
  103. Lee SR, Kwon KS, Kim SR, et al. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem 1998;273(25):15366–15372. DOI: 10.1074/jbc.273.25.15366.
  104. Meng TC, Fukada T, Tonks NK. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 2002;9(2):387–399. DOI: 10.1016/s1097-2765(02)00445-8.
  105. Kwon J, Lee SR, Yang KS, et al. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci U S A 2004;101(47):16419–16424. DOI: 10.1073/pnas.0407396101.
  106. Levinthal DJ, Defranco DB. Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons. J Biol Chem 2005;280(7):5875–5883. DOI: 10.1074/jbc.M410771200.
  107. Kamata H, Honda S, Maeda S, et al. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005;120(5):649–661. DOI: 10.1016/j.cell.2004.12.041.
  108. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003;3(9):745–756. DOI: 10.1038/nri1184.
  109. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003;114(2):181–190. DOI: 10.1016/s0092-8674(03)00521-x.
  110. Liu ZG, Hsu H, Goeddel DV, et al. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 1996;87(3):565–576. DOI: 10.1016/s0092-8674(00)81375-6.
  111. Liu J, Finkel T. Stem cells and oxidants: too little of a bad thing. Cell Metab 2013;18(1):1–2. DOI: 10.1016/j.cmet.2013.06.007.
  112. Xu X, Duan S, Yi F, et al. Mitochondrial regulation in pluripotent stem cells. Cell Metab 2013;18(3):325–332. DOI: 10.1016/j.cmet.2013.06.005.
  113. Hamanaka RB, Glasauer A, Hoover P, et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci Signal 2013;6(261):ra8. DOI: 10.1126/scisignal.2003638.
  114. Facucho-Oliveira JM, Alderson J, Spikings EC, et al. Mitochondrial DNA replication during differentiation of murine embryonic stem cells. J Cell Sci 2007;120(Pt 22):4025–4034. DOI: 10.1242/jcs.016972.
  115. Todd LR, Damin MN, Gomathinayagam R, et al. Growth factor erv1-like modulates Drp1 to preserve mitochondrial dynamics and function in mouse embryonic stem cells. Mol Biol Cell 2010;21(7):1225–1236. DOI: 10.1091/mbc.e09-11-0937.
  116. Orr AL, Vargas L, Turk CN, et al. Suppressors of superoxide production from mitochondrial complex III. Nat Chem Biol 2015;11(11):834–836. DOI: 10.1038/nchembio.1910.
  117. Forristal CE, Wright KL, Hanley NA, et al. Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction 2010;139(1):85–97. DOI: 10.1530/REP-09-0300.
  118. Rahman S. Mitochondrial disease in children. J Intern Med 2020;287(6):609–633. DOI: 10.1111/joim.13054.
  119. Munnich A, Rustin P. Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet 2001;106(1):4–17. DOI: 10.1002/ajmg.1391.
  120. Pirini F, Guida E, Lawson F, et al. Nuclear and mitochondrial DNA alterations in newborns with prenatal exposure to cigarette smoke. Int J Environ Res Public Health 2015;12(2):1135–1155. DOI: 10.3390/ijerph120201135.
  121. Dimauro S, Garone C. Metabolic disorders of fetal life: glycogenoses and mitochondrial defects of the mitochondrial respiratory chain. Semin Fetal Neonatal Med 2011;16(4):181–189. DOI: 10.1016/j.siny.2011.04.010.
  122. Munnich A, Rotig A, Chretien D, et al. Clinical presentations and laboratory investigations in respiratory chain deficiency. Eur J Pediatr 1996;155(4):262–274. DOI: 10.1007/BF02002711.
  123. Gire C, Girard N, Nicaise C, et al. Clinical features and neuroradiological findings of mitochondrial pathology in six neonates. Childs Nerv Syst 2002;18(11):621–628. DOI: 10.1007/s00381-002-0621-0.
  124. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 2003;126(Pt 8):1905–1912. DOI: 10.1093/brain/awg170.
  125. McFarland R, Clark KM, Morris AA, et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet 2002;30(2):145–146. DOI: 10.1038/ng819.
  126. Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 2008;39(4):223–235. DOI: 10.1016/j.pediatrneurol. 2008.07.013.
  127. Piao YS, Tang GC, Yang H, et al. Clinico-neuropathological study of a Chinese case of familial adult Leigh syndrome. Neuropathology 2006;26(3):218–221. DOI: 10.1111/j.1440-1789.2006.00686.x.
  128. Rotig A, Cormier V, Blanche S, et al. Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J Clin Invest 1990;86(5):1601–1608. DOI: 10.1172/JCI114881.
  129. DiMauro S, Nicholson JF, Hays AP, et al. Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency. Trans Am Neurol Assoc 1981;106:205–207. PMID: 6294949.
  130. Horvath R, Kemp JP, Tuppen HA, et al. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 2009;132(Pt 11):3165–3174. DOI: 10.1093/brain/awp221.
  131. Silvestri G, Santorelli FM, Shanske S, et al. A new mtDNA mutation in the tRNA(Leu(UUR)) gene associated with maternally inherited cardiomyopathy. Hum Mutat 1994;3(1):37–43. DOI: 10.1002/humu.1380030107.
  132. Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004;114(4):925–931. DOI: 10.1542/peds.2004-0718.
  133. Shanske S, Coku J, Lu J, et al. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. Arch Neurol 2008;65(3):368–372. DOI: 10.1001/archneurol.2007.67.
  134. Manfredi G, Schon EA, Moraes CT, et al. A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. Neuromuscul Disord 1995;5(5):391–398. DOI: 10.1016/0960-8966(94)00079-o.
  135. Wong LJ. Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve 2007;36(3):279–293. DOI: 10.1002/mus.20807.
  136. Yoneda M, Tanno Y, Horai S, et al. A common mitochondrial DNA mutation in the t-RNA(Lys) of patients with myoclonus epilepsy associated with ragged-red fibers. Biochem Int 1990;21(5):789–796. PMID: 2124116.
  137. Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg 2014;218(6):1148–1155. DOI: 10.1016/j.jamcollsurg.2013.11.015.
  138. Niyazov DM, Kahler SG, Frye RE. Primary mitochondrial disease and secondary mitochondrial dysfunction: importance of distinction for diagnosis and treatment. Mol Syndromol 2016;7(3):122–137. DOI: 10.1159/000446586.
  139. Kirby DM, Salemi R, Sugiana C, et al. NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Invest 2004;114(6):837–845. DOI: 10.1172/JCI20683.
  140. Kodaira M, Hatakeyama H, Yuasa S, et al. Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels. FEBS Open Bio 2015;5:219–225. DOI: 10.1016/j.fob.2015. 03.008.
  141. Mimaki M, Wang X, McKenzie M, et al. Understanding mitochondrial complex I assembly in health and disease. Biochim Biophys Acta 2012;1817(6):851–862. DOI: 10.1016/j.bbabio.2011.08.010.
  142. Ardissone A, Invernizzi F, Nasca A, et al. Mitochondrial leukoencephalopathy and complex II deficiency associated with a recessive SDHB mutation with reduced penetrance. Mol Genet Metab Rep 2015;5:51–54. DOI: 10.1016/j.ymgmr.2015.10.006.
  143. Hoekstra AS, Bayley JP. The role of complex II in disease. Biochim Biophys Acta 2013;1827(5):543–551. DOI: 10.1016/j.bbabio.2012.11.005.
  144. Miyake N, Yano S, Sakai C, et al. Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation. Hum Mutat 2013;34(3):446–452. DOI: 10.1002/humu.22257.
  145. Fellman V. Mitochondrial complex III deficienciesin the newborn infant. Drug Discov Today Dis Mech 2006;3(4):421–427. DOI: 10.1016/j.ddmec.2006.11.007.
  146. Fellman V, Kotarsky H. Mitochondrial hepatopathies in the newborn period. Semin Fetal Neonatal Med 2011;16(4):222–228. DOI: 10.1016/j.siny.2011.05.002.
  147. Fernandez-Vizarra E, Zeviani M. Nuclear gene mutations as the cause of mitochondrial complex III deficiency. Front Genet 2015;6:134. DOI: 10.3389/fgene.2015.00134.
  148. Fellman V. [GRACILE syndrome--a severe neonatal mitochondrial disorder]. Duodecim 2012;128(15):1560–1567. PMID: 22970607.
  149. Available from:
  150. Available from:
  151. Rivner MH, Shamsnia M, Swift TR, et al. Kearns-Sayre syndrome and complex II deficiency. Neurology 1989;39(5):693–696. DOI: 10.1212/wnl.39.5.693.
  152. Mayr JA, Havlickova V, Zimmermann F, et al. Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet 2010;19(17):3430–3439. DOI: 10.1093/hmg/ddq254.
  153. De Meirleir L, Seneca S, Lissens W, et al. Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet 2004;41(2):120–124. DOI: 10.1136/jmg.2003.012047.
  154. Shchelochkov OA, Li FY, Wang J, et al. Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metab 2010;101(2–3):282–285. DOI: 10.1016/j.ymgme.2010.07.012.
  155. Spiegel R, Khayat M, Shalev SA, et al. TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome. J Med Genet 2011;48(3):177–182. DOI: 10.1136/jmg.2010.084608.
  156. Atay Z, Bereket A, Turan S, et al. A novel homozygous TMEM70 mutation results in congenital cataract and neonatal mitochondrial encephalo-cardiomyopathy. Gene 2013;515(1):197–199. DOI: 10.1016/j.gene.2012.11.044.
  157. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142C(2):77–85. DOI: 10.1002/ajmg.c.30087.
  158. Bonnefont JP, Djouadi F, Prip-Buus C, et al. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 2004;25(5–6):495–520. DOI: 10.1016/j.mam.2004.06.004.
  159. Voermans NC, van Engelen BG, Kluijtmans LA, et al. Rhabdomyolysis caused by an inherited metabolic disease: very long-chain acyl-CoA dehydrogenase deficiency. Am J Med 2006;119(2):176–179. DOI: 10.1016/j.amjmed.2005.07.064.
  160. Doi T, Abo W, Tateno M, et al. Milder childhood form of very long-chain acyl-CoA dehydrogenase deficiency in a 6-year-old Japanese boy. Eur J Pediatr 2000;159(12):908–911. DOI: 10.1007/pl0000 8368.
  161. Hoffman JD, Steiner RD, Paradise L, et al. Rhabdomyolysis in the military: recognizing late-onset very long-chain acyl Co-A dehydrogenase deficiency. Mil Med 2006;171(7):657–658. DOI: 10.7205/milmed.171.7.657.
  162. van Maldegem BT, Duran M, Wanders RJ, et al. Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. Journal of the American Medical Association 2006;296(8):943–952. DOI: 10.1001/jama.296.8.943.
  163. Das AM, Illsinger S, Lucke T, et al. Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. Clin Chem 2006;52(3):530–534. DOI: 10.1373/clinchem.2005.062000.
  164. Soares-Fernandes JP, Teixeira-Gomes R, Cruz R, et al. Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings. Pediatric Radiol 2008;38(5):559–562. DOI: 10.1007/s00247-007-0721-9.
  165. Robinson BH, Toone JR, Benedict RP, et al. Prenatal diagnosis of pyruvate carboxylase deficiency. Prenat Diagn 1985;5(1):67–71. DOI: 10.1002/pd.1970050112.
  166. Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician 2006;73(11):1981–1990. PMID: 16770930.
  167. Seow HF, Broer S, Broer A, et al. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet 2004;36(9):1003–1007. DOI: 10.1038/ng1406.
  168. Munnich A, Saudubray JM, Taylor J, et al. Congenital lactic acidosis, alpha-ketoglutaric aciduria and variant form of maple syrup urine disease due to a single enzyme defect: dihydrolipoyl dehydrogenase deficiency. Acta Pa
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.