Roles of Mitochondrial DNA in Energy Metabolism

  • Jiapei Lv
  • Madhav Bhatia
  • Xiangdong WangEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1038)


Mitochondria are independent double-membrane organelles responsible for energy production, specifically by completing oxidative phosphorylation. Mitochondria are essential to regulate energy metabolism, signaling pathways, and cell death. Mitochondrial DNA (mtDNA) can be altered by metabolic disorders, oxidative stress, or inflammation in the progression and development of various diseases. In this chapter, we overview the role of mtDNA in energy metabolism and the diseases that are associated with mtDNA abnormality, with a special focus on the major factors which regulate the mechanism of mtDNA in metabolism.


Mitochondria Metabolism Energy mtDNA Disease 



Electron transport chain


Heavy-strand promoter 1


Light-strand promoter


Mitochondrial DNA


Oxidative phosphorylation


Single-subunit RNA polymerase


Reactive oxygen species


Mitochondrial transcription factor A


Mitochondrial transcription factor B2



The work was supported by the Zhongshan Distinguished Professor Grant (XDW), the National Natural Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010), the Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600, 14431905100), Operation funding of Shanghai Institute of Clinical Bioinformatics, the Ministry of Education for Academic Special Science and Research Foundation for PhD Education (20130071110043), and the National Key Research and Development Program (2016YFC0902400, 2017YFSF090207).


  1. 1.
    Bailey CM, Anderson KS. A mechanistic view of human mitochondrial DNA polymerase gamma: providing insight into drug toxicity and mitochondrial disease. Biochim Biophys Acta. 2010;1213–22:1804. [PMID: 20083238]Google Scholar
  2. 2.
    Martinez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell. 2016;199–209:61. [PMID: 26725009]Google Scholar
  3. 3.
    Zhu LZ, Hou YJ, Zhao M, Yang MF, XT F, Sun JY, et al. Caudatin induces caspase-dependent apoptosis in human glioma cells with involvement of mitochondrial dysfunction and reactive oxygen species generation. Cell Biol Toxicol. 2016;32:333–45. [PMID: 27184666]CrossRefPubMedGoogle Scholar
  4. 4.
    Knez J, Marrachelli VG, Cauwenberghs N, Winckelmans E, Zhang Z, Thijs L, et al. Peripheral blood mitochondrial DNA content in relation to circulating metabolites and inflammatory markers: a population study. PLoS One. 2017;12:e0181036. [PMID: 28704533]CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tranah GJ, Manini TM, Lohman KK, Nalls MA, Kritchevsky S, Newman AB, et al. Mitochondrial DNA variation in human metabolic rate and energy expenditure. Mitochondrion. 2011;11:855–61. [PMID: 21586348]CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Payne BA, Cree L, Chinnery PF. Single-cell analysis of mitochondrial DNA. Methods Mol Biol. 2015;1264:67–76. [PMID: 25631004]CrossRefPubMedGoogle Scholar
  7. 7.
    Hsu HC, Li SJ, Chen CY, Chen MF. Eicosapentaenoic acid protects cardiomyoblasts from lipotoxicity in an autophagy-dependent manner. Cell Biol Toxicol. 2017, July 24. doi: [PMID: 28741157]
  8. 8.
    Devine H, Patani R. The translational potential of human induced pluripotent stem cells for clinical neurology: the translational potential of hiPSCs in neurology. Cell Biol Toxicol. 2017;33:129–44. [PMID: 27915387]CrossRefPubMedGoogle Scholar
  9. 9.
    Sologub M, Litonin D, Anikin M, Mustaev A, Temiakov D. TFB2 is a transient component of the catalytic site of the human mitochondrial RNA polymerase. Cell. 2009;139:934–44. [PMID: 19945377]CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Fathi H, Ebrahimzadeh MA, Ziar A, Mohammadi H. Oxidative damage induced by retching; antiemetic and neuroprotective role of Sambucus Ebulus L. Cell Biol Toxicol. 2015;31:231–9. [PMID: 26493312]CrossRefPubMedGoogle Scholar
  11. 11.
    Kaarniranta K, Tokarz P, Koskela A, Paterno J, Blasiak J. Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration. Cell Biol Toxicol. 2017;33:113–28. [PMID: 27900566]CrossRefPubMedGoogle Scholar
  12. 12.
    Vedi M, Sabina EP. Assessment of hepatoprotective and nephroprotective potential of withaferin a on bromobenzene-induced injury in Swiss albino mice: possible involvement of mitochondrial dysfunction and inflammation. Cell Biol Toxicol. 2016;32:373–90. [PMID: 27250656]CrossRefPubMedGoogle Scholar
  13. 13.
    Zerin T, Kim JS, Gil HW, Song HY, Hong SY. Effects of formaldehyde on mitochondrial dysfunction and apoptosis in SK-N-SH neuroblastoma cells. Cell Biol Toxicol. 2015;31:261–72. [PMID: 26728267]CrossRefPubMedGoogle Scholar
  14. 14.
    Rotig A. Genetics of mitochondrial respiratory chain deficiencies. Rev Neurol. 2014;170:309–22. [PMID: 24798924]CrossRefPubMedGoogle Scholar
  15. 15.
    Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem. 1955;217:409–27. [PMID: 13271404]PubMedGoogle Scholar
  16. 16.
    Thorburn DR, Sugiana C, Salemi R, Kirby DM, Worgan L, Ohtake A, et al. Biochemical and molecular diagnosis of mitochondrial respiratory chain disorders. Biochim Biophys Acta. 2004;1659:121–8. [PMID: 15576043]CrossRefPubMedGoogle Scholar
  17. 17.
    Wallace DC, Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol. 2013;a021220:5. [PMID: 24186072]Google Scholar
  18. 18.
    Larsson NG. Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem. 2010;683–706:79. [PMID: 20350166]Google Scholar
  19. 19.
    Campbell GR, Reeve A, Ziabreva I, Polvikoski TM, Taylor RW, Reynolds R, et al. Mitochondrial DNA deletions and depletion within paraspinal muscles. Neuropathol Appl Neurobiol. 2013;39:377–89. [PMID: 22762368]CrossRefPubMedGoogle Scholar
  20. 20.
    Goffart S, Kleist-Retzow v. JC, Wiesner RJ. Regulation of mitochondrial proliferation in the heart: power-plant failure contributes to cardiac failure in hypertrophy. Cardiovasc Res. 2004;64:198–207. [PMID: 15485678]CrossRefPubMedGoogle Scholar
  21. 21.
    Chinnery PF. Mitochondrial Disorders Overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle;1993.Google Scholar
  22. 22.
    Holmgren D, Wahlander H, Eriksson BO, Oldfors A, Holme E, Tulinius M. Cardiomyopathy in children with mitochondrial disease; clinical course and cardiological findings. Eur Heart J. 2003;24:280–8. [PMID: 12590906]CrossRefPubMedGoogle Scholar
  23. 23.
    Fassone E, Rahman S. Complex I Deficiency: clinical features, biochemistry and molecular genetics. J Med Genet. 2012;49:578–90. [PMID: 22972949]CrossRefPubMedGoogle Scholar
  24. 24.
    Hagen CM, Aidt FH, Havndrup O, Hedley PL, Jespersgaard C, Jensen M, et al. MT-CYB mutations in hypertrophic cardiomyopathy. Mol Genet Genomic Med. 2013;1:54–65. [PMID: 24498601]CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Marin-Garcia J, Goldenthal MJ, Ananthakrishnan R, Pierpont ME. The complete sequence of mtDNA genes in idiopathic dilated cardiomyopathy shows novel missense and tRNA mutations. J Card Fail. 2000;6:321–9. [PMID: 11145757]CrossRefPubMedGoogle Scholar
  26. 26.
    Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 2012;485:251–5. [PMID: 22535248]CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Villarroya J, Dorado B, Vila MR, Garcia-Arumi E, Domingo P, Giralt M, et al. Thymidine kinase 2 deficiency-induced mitochondrial DNA depletion causes abnormal development of adipose tissues and adipokine levels in mice. PLoS One. 2011;6:e29691. [PMID: 22216345]CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wu Y, Geng XC, Wang JF, Miao YF, YL L, Li B. The HepaRG cell line, a superior in vitro model to L-02, HepG2 and hiHeps cell lines for assessing drug-induced liver injury. Cell Biol Toxicol. 2016;32:37–59. [PMID: 27027780]CrossRefPubMedGoogle Scholar
  29. 29.
    Fierbinteanu-Braticevici C, Sinescu C, Moldoveanu A, Petrisor A, Diaconu S, Cretoiu D, et al. Nonalcoholic fatty liver disease: one entity, multiple impacts on liver health. Cell Biol Toxicol. 2017;33:5–14. [PMID: 27680752]CrossRefPubMedGoogle Scholar
  30. 30.
    Ganta KK, Mandal A, Chaubey B. Depolarization of mitochondrial membrane potential is the initial event in non-nucleoside reverse transcriptase inhibitor efavirenz induced cytotoxicity. Cell Biol Toxicol. 2017;33:69–82. [PMID: 27639578]CrossRefPubMedGoogle Scholar
  31. 31.
    Liu T, Liu WH, Zhao JS, Meng FZ, Wang H. Lutein protects against beta-amyloid peptide-induced oxidative stress in cerebrovascular endothelial cells through modulation of Nrf-2 and NF-kappab. Cell Biol Toxicol. 2017;33:57–67. [PMID: 27878403]CrossRefPubMedGoogle Scholar
  32. 32.
    Nomoto K, Tsuneyama K, Takahashi H, Murai Y, Takano Y. Cytoplasmic fine granular expression of 8-hydroxydeoxyguanosine reflects early mitochondrial oxidative DNA damage in nonalcoholic fatty liver disease. AIMM. 2008;71–5:16. [PMID: 18091316]Google Scholar
  33. 33.
    Kawahara H, Fukura M, Tsuchishima M, Takase S. Mutation of mitochondrial DNA in livers from patients with alcoholic hepatitis and nonalcoholic steatohepatitis. Alcohol Clin Exp Res. 2007;31:S54–60. [PMID: 17331167]CrossRefPubMedGoogle Scholar
  34. 34.
    Zhou X, Kannisto K, Curbo S, von Dobeln U, Hultenby K, Isetun S, et al. Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect beta-oxidation. PLoS One. 2013;8:e58843. [PMID: 23505564]CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wada J, Nakatsuka A. Mitochondrial dynamics and mitochondrial dysfunction in diabetes. Acta Med Okayama. 2016;70:151–8. [PMID: 27339203]PubMedGoogle Scholar
  36. 36.
    Wang L. Mitochondrial purine and pyrimidine metabolism and beyond. Nucleosides Nucleotides Nucleic Acids. 2016;35:578–94. [PMID: 27906631]CrossRefPubMedGoogle Scholar
  37. 37.
    Kaufman BA, Li C, Soleimanpour SA. Mitochondrial regulation of beta-cell function: maintaining the momentum for insulin release. Mol Asp Med. 2015;42:91–104. [PMID: 25659350]CrossRefGoogle Scholar
  38. 38.
    Malik AN, Czajka AI. Mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion. 2013;13:481–92. [PMID: 23085537]CrossRefPubMedGoogle Scholar
  39. 39.
    Falkenberg M, Gaspari M, Rantanen A, Trifunovic A, Larsson NG, Gustafsson CM. Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. Nat Genet. 2002;31:289–94. [PMID: 12068295]CrossRefPubMedGoogle Scholar
  40. 40.
    Cree LM, Patel SK, Pyle A, Lynn S, Turnbull DM, Chinnery PF, et al. Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets. Diabetologia. 2008;51:1440–3. [PMID: 18528676]CrossRefPubMedGoogle Scholar
  41. 41.
    Damas J, Samuels DC, Carneiro J, Amorim A, Pereira F. Mitochondrial DNA rearrangements in health and disease--a comprehensive study. Hum Mutat. 2014;35:1–14. [PMID: 24115352]CrossRefPubMedGoogle Scholar
  42. 42.
    Fernandez-Silva P, Enriquez JA, Montoya J. Replication and transcription of mammalian mitochondrial DNA. Exp Physiol. 2003;88:41–56. [PMID: 12525854]CrossRefPubMedGoogle Scholar
  43. 43.
    Asin-Cayuela J, Gustafsson CM. Mitochondrial transcription and its regulation in mammalian cells. Trends Biochem Sci. 2007;32:111–7. [PMID: 17291767]CrossRefPubMedGoogle Scholar
  44. 44.
    Koeck T, Olsson AH, Nitert MD, Sharoyko VV, Ladenvall C, Kotova O, et al. A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes. Cell Metab. 2011;13:80–91. [PMID: 21195351]CrossRefPubMedGoogle Scholar
  45. 45.
    Metodiev MD, Lesko N, Park CB, Camara Y, Shi Y, Wibom R, et al. Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome. Cell Metab. 2009;9:386–97. [PMID: 19356719]CrossRefPubMedGoogle Scholar
  46. 46.
    Raimundo N, Song L, Shutt TE, McKay SE, Cotney J, Guan MX, et al. Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell. 2012;148:716–26. [PMID: 22341444]CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Moustafa IM, Uchida A, Wang Y, Yennawar N, Cameron CE. Structural models of mammalian mitochondrial transcription factor B2. Biochim Biophys Acta. 2015;987–1002:1849. [PMID: 26066983]Google Scholar
  48. 48.
    Bao L, Diao H, Dong N, Su X, Wang B, Mo Q, et al. Histone deacetylase inhibitor induces cell apoptosis and cycle arrest in lung cancer cells via mitochondrial injury and p53 up-acetylation. Cell Biol Toxicol. 2016;32:469–82. [PMID: 27423454]CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Guja KE, Venkataraman K, Yakubovskaya E, Shi H, Mejia E, Hambardjieva E, et al. Structural basis for S-adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1. Nucleic Acids Res. 2013;41:7947–59. [PMID: 23804760]CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mangus DA, Jang SH, Jaehning JA. Release of the yeast mitochondrial RNA polymerase specificity factor from transcription complexes. J Biol Chem. 1994;269:26568–74. [PMID: 7929382]PubMedGoogle Scholar
  51. 51.
    Litonin D, Sologub M, Shi Y, Savkina M, Anikin M, Falkenberg M, et al. Human mitochondrial transcription revisited: only TFAM and TFB2M are required for transcription of the mitochondrial genes in vitro. J Biol Chem. 2010;285:18129–33. [PMID: 20410300]CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Dairaghi DJ, Shadel GS, Clayton DA. Human mitochondrial transcription factor a and promoter spacing integrity are required for transcription initiation. Biochim Biophys Acta. 1995;1271:127–34. [PMID: 7599198]CrossRefPubMedGoogle Scholar
  53. 53.
    Nicholas LM, Valtat B, Medina A, Andersson L, Abels M, Mollet IG, et al. Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic beta-cells. Mol Metabol. 2017;6:651–63. [PMID: 28702322]CrossRefGoogle Scholar
  54. 54.
    Shi Y, Dierckx A, Wanrooij PH, Wanrooij S, Larsson NG, Wilhelmsson LM, et al. Mammalian transcription factor a is a core component of the mitochondrial transcription machinery. Proc Natl Acad Sci U S A. 2012;109:16510–5. [PMID: 23012404]CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ramachandran A, Basu U, Sultana S, Nandakumar D, Patel SS. Human mitochondrial transcription factors TFAM and TFB2M work synergistically in promoter melting during transcription initiation. Nucleic Acids Res. 2017;45:861–74. [PMID: 27903899]CrossRefPubMedGoogle Scholar
  56. 56.
    Rantanen A, Jansson M, Oldfors A, Larsson NG. Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis. Mamm Genome Off J Int Mamm Genome Soc. 2001;12:787–92. [PMID: 11668394]CrossRefGoogle Scholar
  57. 57.
    McCulloch V, Seidel-Rogol BL, Shadel GSA. Human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Mol Cell Biol. 2002;22:1116–25. [PMID: 11809803]CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Soltani B, Ghaemi N, Sadeghizadeh M, Najafi F. Curcumin confers protection to irradiated THP-1 cells while its nanoformulation sensitizes these cells via apoptosis induction. Cell Biol Toxicol. 2016;32:543–61. [PMID: 27473378]CrossRefPubMedGoogle Scholar
  59. 59.
    Steinberg P, Behnisch PA, Besselink H, Brouwer AA. Screening of molecular cell targets for carcinogenic heterocyclic aromatic amines by using CALUX(R) reporter gene assays. Cell Biol Toxicol. 2017;33:283–93. [PMID: 27942899]CrossRefPubMedGoogle Scholar
  60. 60.
    Leclerc E, Hamon J, Claude I, Jellali R, Naudot M, Bois F. Investigation of acetaminophen toxicity in HepG2/C3a microscale cultures using a system biology model of glutathione depletion. Cell Biol Toxicol. 2015;31:173–85. [PMID: 25956491]CrossRefPubMedGoogle Scholar
  61. 61.
    Denardin CC, Martins LA, Parisi MM, Vieira MQ, Terra SR, Barbe-Tuana FM, et al. Autophagy induced by purple pitanga (Eugenia Uniflora L.) extract triggered a cooperative effect on inducing the hepatic stellate cell death. Cell Biol Toxicol. 2017;33:197–206. [PMID: 27744523]CrossRefPubMedGoogle Scholar
  62. 62.
    Lippai M, Szatmari Z. Autophagy-from molecular mechanisms to clinical relevance. Cell Biol Toxicol. 2017;33:145–68. [PMID: 27957648]CrossRefPubMedGoogle Scholar
  63. 63.
    Imhoff BR, Hansen JM. Tert-butylhydroquinone induces mitochondrial oxidative stress causing Nrf2 activation. Cell Biol Toxicol. 2010;26:541–51. [PMID: 20429028]CrossRefPubMedGoogle Scholar
  64. 64.
    Cristofori P, Sauer AV, Trevisan A. Three common pathways of nephrotoxicity induced by halogenated alkenes. Cell Biol Toxicol. 2015;31:1–13. [PMID: 25665826]CrossRefPubMedGoogle Scholar
  65. 65.
    Zhang X, Yin H, Li Z, Zhang T, Yang Z. Nano-TiO2 induces autophagy to protect against cell death through antioxidative mechanism in podocytes. Cell Biol Toxicol. 2016;32:513–27. [PMID: 27430495]CrossRefPubMedGoogle Scholar
  66. 66.
    Wang W, Gao D, Wang X. Can single-cell RNA sequencing crack the mystery of cells? Cell Biol Toxicol. 2017, July 21. doi: [PMID: 28733864]
  67. 67.
    Wang W, Wang X, Single-cell CRISPR. Screening in drug resistance. Cell Biol Toxicol. 2017;33:207–10. [PMID: 28474250]CrossRefPubMedGoogle Scholar
  68. 68.
    Wang X. New biomarkers and therapeutics can be discovered during COPD-lung cancer transition. Cell Biol Toxicol. 2016;32:359–61. [PMID: 27405768]CrossRefPubMedGoogle Scholar

Copyright information

© The Editor(s) (if applicable) and The Author(s) 2018 2017

Authors and Affiliations

  1. 1.Zhongshan Hospital Institute of Fudan UniversityShanghai Medical SchoolShanghaiChina
  2. 2.Department of PathologyUniversity of OtagoWellingtonNew Zealand
  3. 3.Zhongshan Hospital Institute of Clinical ScienceFudan University, Shanghai Medical CollegeShanghaiChina

Personalised recommendations