Mitochondrial DNA Methylation and Related Disease

  • Danyan Gao
  • Bijun Zhu
  • Hongzhi SunEmail author
  • Xiangdong WangEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1038)


Most researchers focused on methylation of genomic DNA, while methylation of mitochondrial DNA (mtDNA) is rarely tauched, and there is still controversy about the existence of mtDNA methylation. The study of cytosine methylation in mtDNA is limited. The mtDNA was recently found to exist CpG hypomethylation, and more studies provided evidence that mtDNA methylation plays an important role in mitochondrial gene regulation. In present review, we will overview recent studies of mitochondrial DNA methylation and potential influencing factors in diseases that are involved in mtDNA methylation. Thus, the further studies on mtDNA methylation will provide more evidence to explain the mechanism of mtDNA methylation and an advantageous approach for human clinical diagnosis and prevention.


Mitochondrial DNA Methylation 



The work was supported by the Zhongshan Distinguished Professor Grant (XDW), the National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010), the Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600, 14431905100), the 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.
    Brandon MC, Lott MT, Nguyen KC, Spolim S, Navathe SB, Baldi P, et al. MITOMAP: a human mitochondrial genome database – 2004 update. Nucleic Acids Res. 2005;33:D611–3. [PMID: 15608272]CrossRefPubMedGoogle Scholar
  2. 2.
    Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a Dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407. [PMID: 16285865]CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Paes B, Moco PD, Pereira CG, Porto GS, de Sousa Russo EM, Reis LCJ, et al. Ten years of iPSC: clinical potential and advances in vitro hematopoietic differentiation. Cell Biol Toxicol. 2017;33:233–50. [PMID: 28039590]CrossRefPubMedGoogle Scholar
  4. 4.
    Janssen BG, Byun HM, Roels HA, Gyselaers W, Penders J, Baccarelli AA, et al. Regulating role of fetal thyroid hormones on placental mitochondrial DNA methylation: epidemiological evidence from the ENVIRONAGE birth cohort study. Clin Epigenetics. 2017;9:66. [PMID: 28649287]CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Byun HM, Panni T, Motta V, Hou L, Nordio F, Apostoli P, et al. Effects of airborne pollutants on mitochondrial DNA methylation. Part Fibre Toxicol. 2013;10:18. [PMID: 23656717]CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SMDNA. Methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011;108:3630–5. [PMID: 21321201]CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dawid IB. 5-methylcytidylic acid: absence from mitochondrial DNA of frogs and HeLa cells. Science. 1974;184:80–1. [PMID: 4815287]CrossRefPubMedGoogle Scholar
  8. 8.
    Choi YS, Hoon Jeong J, Min HK, Jung HJ, Hwang D, Lee SW, et al. Shot-gun proteomic analysis of mitochondrial D-loop DNA binding proteins: identification of mitochondrial histones. Mol BioSyst. 2011;7:1523–36. [PMID: 21359316]CrossRefPubMedGoogle Scholar
  9. 9.
    Hong EE, Okitsu CY, Smith AD, Hsieh CL. Regionally specific and genome-wide analyses conclusively demonstrate the absence of CpG methylation in human mitochondrial DNA. Mol Cell Biol. 2013;33:2683–90. [PMID: 23671186]CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Manev H, Dzitoyeva S. Progress in mitochondrial epigenetics. Biomol Concepts. 2013;4:381–9. [PMID: 25436587]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.
    Giromini C, Rebucci R, Fusi E, Rossi L, Saccone F, Baldi A. Cytotoxicity, apoptosis, DNA damage and methylation in mammary and kidney epithelial cell lines exposed to ochratoxin A. Cell Biol Toxicol. 2016;32:249–58. [PMID: 27154019]CrossRefPubMedGoogle Scholar
  13. 13.
    Gomez-Sagasti MT, Becerril JM, Epelde L, Alkorta I, Garbisu C. Early gene expression in Pseudomonas fluorescens exposed to a polymetallic solution. Cell Biol Toxicol. 2015;31:39–81. [PMID: 25754557]CrossRefPubMedGoogle Scholar
  14. 14.
    Santamaria E, Avila MA, Latasa MU, Rubio A, Martin-Duce A, SC L, et al. Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine. Proc Natl Acad Sci U S A. 2003;100:3065–70. [PMID: 12631701]CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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
  16. 16.
    van der Wijst MG, van Tilburg AY, Ruiters MH, Rots MG. Experimental mitochondria-targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential regulator of mitochondrial gene expression. Sci Rep. 2017;7:177. [PMID: 28282966]CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rinaldi L, Avgustinova A, Martin M, Datta D, Solanas G, Prats N, et al. Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-gamma. elife. 2017;6:e21697. [PMID: 28425913]CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Guney Eskiler G, Cecener G, Tunca B, Egeli U. An in vitro model for the development of acquired tamoxifen resistance. Cell Biol Toxicol. 2016;32:563–81. [PMID: 27585693]CrossRefPubMedGoogle Scholar
  19. 19.
    Chen T, Hevi S, Gay F, Tsujimoto N, He T, Zhang B, et al. Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nat Genet. 2007;39:391–6. [PMID: 17322882]CrossRefPubMedGoogle Scholar
  20. 20.
    Wang XCBT. Profiles of cabozantinib approved for advanced renal cell carcinomas. Cell Biol Toxicol. 2016;32:259–61. [PMID: 27383755]CrossRefPubMedGoogle Scholar
  21. 21.
    Mohsenzadeh M, Sadeghi RN, Vahedi M, Kamani F, Hashemi M, Asadzadeh H, et al. Promoter hypermethylation of RAR-beta tumor suppressor gene in gastric carcinoma: association with histological type and clinical outcomes. Cancer Biomark. 2017;20:7–15. [PMID: 28759951]CrossRefPubMedGoogle Scholar
  22. 22.
    Lodeiro MF, Uchida A, Bestwick M, Moustafa IM, Arnold JJ, Shadel GS, et al. Transcription from the second heavy-strand promoter of human mtDNA is repressed by transcription factor A in vitro. Proc Natl Acad Sci U S A. 2012;109:6513–8. [PMID: 22493245]CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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
  24. 24.
    Lippai M, Szatmari Z. Autophagy-from molecular mechanisms to clinical relevance. Cell Biol Toxicol. 2017;33:145–68. [PMID: 27957648]CrossRefPubMedGoogle Scholar
  25. 25.
    Stoccoro A, Siciliano G, Migliore L, Coppede F. Decreased methylation of the mitochondrial D-loop region in late-onset Alzheimer’s disease. J Alzheimers Dis. 2017;59:559–64. [PMID: 28655136]CrossRefPubMedGoogle Scholar
  26. 26.
    Cacabelos R, Torrellas C. Epigenetics of aging and Alzheimer’s disease: implications for pharmacogenomics and drug response. Int J Mol Sci. 2015;16:30483–543. [PMID: 26703582]CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhou Y, Ning Z, Lee Y, Hambly BD, McLachlan CS. Shortened leukocyte telomere length in type 2 diabetes mellitus: genetic polymorphisms in mitochondrial uncoupling proteins and telomeric pathways. Clin Transl Med. 2016;5:8. [PMID: 26951191]CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zheng LD, Linarelli LE, Brooke J, Smith C, Wall SS, Greenawald MH, et al. Mitochondrial epigenetic changes link to increased diabetes risk and early-stage prediabetes indicator. Oxidative Med Cell Longev. 2016;2016:5290638. [PMID: 27298712]Google Scholar
  29. 29.
    Miko E, Vida A, Bai P. Translational aspects of the microbiome-to be exploited. Cell Biol Toxicol. 2016;32:153–6. [PMID: 27098154]CrossRefPubMedGoogle Scholar
  30. 30.
    Cao T, Yang D, Zhang X, Wang Y, Qiao Z, Gao L, et al. FAM3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling. Cell Biol Toxicol. 2017;33:457–66. [PMID: 28247283]CrossRefGoogle Scholar
  31. 31.
    Kuznetsova T, Knez J. Peripheral blood mitochondrial DNA and myocardial function. Adv Exp Med Biol. 2017;982:347–58. [PMID: 28551797]CrossRefPubMedGoogle Scholar
  32. 32.
    Hulman A, Simmons RK, Brunner EJ, Witte DR, Faerch K, Vistisen D, et al. Trajectories of glycaemia, insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes: a longitudinal analysis from the Whitehall II cohort study. Diabetologia. 2017;60:1252–60. [PMID: 28409212]CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012;379:2279–90. [PMID: 22683128]CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    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
  35. 35.
    O’Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell. 2011;20:606–19. [PMID: 22094255]CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Seo JB, Jung SR, Hille B, Koh DS, Extracellular ATP. Protects pancreatic duct epithelial cells from alcohol-induced damage through P2Y1 receptor-cAMP signal pathway. Cell Biol Toxicol. 2016;32:229–47. [PMID: 27197531]CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Amodio G, Sasso E, D’Ambrosio C, Scaloni A, Moltedo O, Franceschelli S, et al. Identification of a microRNA (miR-663a) induced by ER stress and its target gene PLOD3 by a combined microRNome and proteome approach. Cell Biol Toxicol. 2016;32:285–303. [PMID: 27233793]CrossRefPubMedGoogle Scholar
  38. 38.
    Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, Olashaw N, et al. SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol Cell Biol. 2011;31:4720–34. [PMID: 21947282]CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Engin AB, Engin A. The interactions between Kynurenine, folate, methionine and Pteridine pathways in obesity. Adv Exp Med Biol. 2017;960:511–27. [PMID: 28585214]CrossRefPubMedGoogle Scholar
  40. 40.
    Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300:1140–2. [PMID: 12750520]CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Infantino V, Castegna A, Iacobazzi F, Spera I, Scala I, Andria G, et al. Impairment of methyl cycle affects mitochondrial methyl availability and glutathione level in Down’s syndrome. Mol Genet Metab. 2011;102:378–82. [PMID: 21195648]CrossRefPubMedGoogle Scholar
  42. 42.
    Peng C, Bind MC, Colicino E, Kloog I, Byun HM, Cantone L, et al. Particulate air pollution and fasting blood glucose in nondiabetic individuals: associations and epigenetic mediation in the normative aging study, 2000–2011. Environ Health Perspect. 2016;124:1715–21. [PMID: 27219535]CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zheng LD, Linarelli LE, Liu L, Wall SS, Greenawald MH, Seidel RW, et al. Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans. Clin Epigenetics. 2015;7:60. [PMID: 26110043]CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Thomas PD, Kahn M. Kat3 coactivators in somatic stem cells and cancer stem cells: biological roles, evolution, and pharmacologic manipulation. Cell Biol Toxicol. 2016;32:61–81. [PMID: 27008332]CrossRefPubMedGoogle Scholar
  45. 45.
    Bellizzi D, D’Aquila P, Scafone T, Giordano M, Riso V, Riccio A, et al. The control region of mitochondrial DNA shows an unusual CpG and non-CpG methylation pattern. DNA Res. 2013;20:537–47. [PMID: 23804556]CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    He J, Mao CC, Reyes A, Sembongi H, Di Re M, Granycome C, et al. The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization. J Cell Biol. 2007;176:141–6. [PMID: 17210950]CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Sidor-Kaczmarek J, Cichorek M, Spodnik JH, Wojcik S, Morys J. Proteasome inhibitors against amelanotic melanoma. Cell Biol Toxicol. 2017, March 9. doi: [PMID: 28281027]
  48. 48.
    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
  49. 49.
    Bao L, Zhang Y, Wang J, Wang H, Dong N, Su X, et al. Variations of chromosome 2 gene expressions among patients with lung cancer or non-cancer. Cell Biol Toxicol. 2016;32:419–35. [PMID: 27301951]CrossRefPubMedGoogle Scholar
  50. 50.
    Ohashi K, Munetsuna E, Yamada H, Ando Y, Yamazaki M, Taromaru N, et al. High fructose consumption induces DNA methylation at PPARalpha and CPT1A promoter regions in the rat liver. Biochem Biophys Res Commun. 2015;468:185–9. [PMID: 26519879]CrossRefPubMedGoogle Scholar
  51. 51.
    Gao X, Liu YA. Transcriptomic study suggesting human iPSC-derived hepatocytes potentially offer a better in vitro model of hepatotoxicity than most hepatoma cell lines. Cell Biol Toxicol. 2017;33:407–21. [PMID: 28144825]CrossRefPubMedGoogle Scholar
  52. 52.
    Yamazaki M, Munetsuna E, Yamada H, Ando Y, Mizuno G, Murase Y, et al. Fructose consumption induces hypomethylation of hepatic mitochondrial DNA in rats. Life Sci. 2016;149:146–52. [PMID: 26869391]CrossRefPubMedGoogle Scholar
  53. 53.
    Crott JW, Choi SW, Branda RF, Mason JB. Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Mutat Res. 2005;570:63–70. [PMID: 15680403]CrossRefPubMedGoogle Scholar
  54. 54.
    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
  55. 55.
    Kang SJ, Lee HM, Park YI, Yi H, Lee H. So B, et al. chemically induced hepatotoxicity in human stem cell-induced hepatocytes compared with primary hepatocytes and HepG2. Cell Biol Toxicol. 2016;32:403–17. [PMID: 27287938]CrossRefPubMedGoogle Scholar
  56. 56.
    Blanch M, Mosquera JL, Ansoleaga B, Ferrer I, Barrachina M, Altered Mitochondrial DNA. Methylation pattern in Alzheimer disease-related pathology and in Parkinson disease. Am J Pathol. 2016;186:385–97. [PMID: 26776077]CrossRefPubMedGoogle Scholar
  57. 57.
    Domcke S, Bardet AF, Adrian Ginno P, Hartl D, Burger L, Schubeler D. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature. 2015;528:575–9. [PMID: 26675734]CrossRefPubMedGoogle Scholar
  58. 58.
    Kornicka K, Marycz K, Maredziak M, Tomaszewski KA, Nicpon J. The effects of the DNA methyltranfserases inhibitor 5-Azacitidine on ageing, oxidative stress and DNA methylation of adipose derived stem cells. J Cell Mol Med. 2017;21:387–401. [PMID: 27998022]CrossRefPubMedGoogle Scholar
  59. 59.
    Gu J, Wang X. New future of cell biology and toxicology: thinking deeper. Cell Biol Toxicol. 2016;32:1–3. [PMID: 26874518]CrossRefPubMedGoogle Scholar
  60. 60.
    Kelly RD, Mahmud A, McKenzie M, Trounce IA, St John JC. Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A. Nucleic Acids Res. 2012;40:10124–38. [PMID: 22941637]CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Bestwick ML, Shadel GS. Accessorizing the human mitochondrial transcription machinery. Trends Biochem Sci. 2013;38:283–91. [PMID: 23632312]CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    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-kappa b. Cell Biol Toxicol. 2017;33:57–67. [PMID: 27878403]CrossRefPubMedGoogle Scholar
  63. 63.
    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
  64. 64.
    Wang W, Wang X, Single-cell CRISPR. Screening in drug resistance. Cell Biol Toxicol. 2017;33:207–10. [PMID: 28474250]CrossRefPubMedGoogle Scholar
  65. 65.
    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]
  66. 66.
    Wang W, Zhu B, Wang X. Dynamic phenotypes: illustrating a single-cell odyssey. Cell Biol Toxicol. 2017;33:423–7. [PMID: 28638956]CrossRefGoogle Scholar
  67. 67.
    Liu B, Du Q, Chen L, Fu G, Li S, Fu L, et al. CpG methylation patterns of human mitochondrial DNA. Sci Rep. 2016;6:23421. [PMID: 26996456]CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Zhongshan Hospital Institute of Clinical ScienceFudan University Medical SchoolShanghaiChina
  2. 2.Shanghai Institute of Clinical BioinformaticsShanghaiChina
  3. 3.Liaoning Province Key Laboratory of Cancer MetabolomicsJinzhou Hospital of Jinzhou Medical UniversityJinzhouChina
  4. 4.Zhongshan Hospital Institute of Clinical ScienceFudan University, Shanghai Medical CollegeShanghaiChina

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