Research Progress of Mitochondrial DNA and Cancer

  • Dengsheng Guo Changzhi Medical College/Minimally Invasive Spine Department, Jincheng General Hospital
  • Jiangtao Jin Changzhi Medical College/Minimally Invasive Spine Department, Jincheng General Hospital
  • Deqiang Gao Changzhi Medical College/Minimally Invasive Spine Department, Jincheng General Hospital
  • Yuanyuan Wei Shaanxi University of Chinese Medicine
  • Xiaojun XuYuanyuanWei Shaanxi University of Chinese Medicine
  • Tianlei SunYuanyuanWei Shaanxi University of Chinese Medicine
Keywords: Mitochondrial DNAMutation; Mitochondrial DNACopy Number; Cancer


Mitochondrial DNAmutation will lead to a series of diseases, and Defective mitochondrial DNAwill lead to organ dysfunction.The increase of mutation frequency caused by nuclear DNArepair defect, replication error, carcinogen exposure and aging is generally consid-ered to drive the occurrence of cancer.In contrast, the status and role of mitochondrial genome mutation in cancer are not clear.We reviewed the variation in number and structure of mtDNAin colorectal cancer, liver cancer, breast cancer , aiming to illustrate the important role of mtDNAin the occurrence and development of cancer, and to provide some reference for early diagnosis, treatment and prognosis evaluation of cancer.


[1] Yan C, Duanmu X, Zeng L, Liu B, Song Z.Mitochondrial DNA: Distribution, Mutations, and Elimination. Cells. 2019; 8(4):379.

[2] Zong WX, Rabinowitz JD, White E.Mitochondria and Cancer. Mol Cell. 2016; 61(5): 667-676.

[3] Yuan Y, Ju YS, Kim Y, et al.Comprehensive molecular characterization of mitochondrial genomes in human cancers [published

correction appears in Nat Genet.2020 Feb 11;:] [published correction appears in Nat Genet.2020 Apr 27;:].Nat Genet. 2020; 52(3):342-352.

[4] Reznik E, Miller ML, Şenbabaoğlu Y, et al.Mitochondrial DNA copy number variation across human cancers.Elife.2016;5:e10769.

Published 2016 Feb 22.

[5] Desagher S., Martinou J.C.Mitochondria as the central control point of apoptosis.Trends Cell Biol.2000;10:369–377.

[6] Suen D.F., Norris K.L., Youle R.J.Mitochondrial dynamics and apoptosis.Genes Dev. 2008; 22:1577–1590.

[7] Arakaki N., Nishihama T., Owaki H., Kuramoto Y., Suenaga M., Miyoshi E., Emoto Y., Shibata H., Shono M., Higuti T.Dynamics

of mitochondria during the cell cycle.Biol.Pharm.Bull.2006;29:1962–1965.

[8] Finkel T., Hwang P.M.The Krebs cycle meets the cell cycle: Mitochondria and the G(1)-S transition.Proc.Natl.Acad.Sci.


[9] Mishra P., Chan D.C.Mitochondrial dynamics and inheritance during cell division, development and disease.Nat.Rev.Mol.Cell


[10] Nicholls T.J., Gustafsson C.M. Separating and Segregating the Human Mitochondrial Genome. Trends Biochem.Sci.2018;43:869–


[11] Holt I.J., Reyes A.Human mitochondrial DNA replication.Cold Spring Harb. Perspect. Biol.2012;4:a012971.

[12] Ingman M., Kaessmann H., Paabo S., Gyllensten U.Mitochondrial genome variation and the origin of modern humans.Na_x005fture.2000;408:708–713.

[13] Yuan R.T., Sun Y., Bu L.X., Jia M.Y.Gene mutations in the D-loop region of mitochondrial DNA in oral squamous cell carcinoma.

Mol. Med.Rep. 2015; 11: 4496 –4500.

[14] Nicolson GL. Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements.Integr Med (Encinitas).2014;13(4):35-43.

[15] Guyatt AL, Burrows K, Guthrie PAI, et al.Cardiometabolic phenotypes and mitochondrial DNA copy number in two cohorts of

UK women. Mitochondrion. 2018; 39: 9-19.

[16] Pello R, Martín MA, Carelli V, et al. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in

a cellular model of mitochondrial disease.Hum Mol Genet.2008 Dec 15;17(24):4001-11.

[17] Larman TC, DePalma SR, Hadjipanayis AG, Protopopov A, Zhang J, Gabriel SB, Chin L, Seidman CE, Kucherlapati R and

Seidman JG; Cancer Genome Atlas Research Network: Spectrum of somatic mitochondrial mutations in five cancers. Proc Natl Acad Sci


[18] Jiménez-Morales S, Pérez-Amado CJ, Langley E, Hidalgo-Miranda A. Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review). Int J Oncol.2018 Sep;53(3):923-936.

[19] Reznik E, Miller ML, Şenbabaoğlu Y, et al: Mitochondrial DNA copy number variation across human cancers.eLife.5:e107692016.

[20] Thyagarajan B, Guan W, Fedirko V, et al. No association between mitochondrial DNA copy number and colorectal adenomas. Mol

Carcinog. 2016;55(8):1290-1296.

[21] Lin PC, Lin JK, Yang SH, et al. Expression of beta-F1-ATPase and mitochondrial transcription factor A and the change in mitochondrial DNA content in colorectal cancer: clinical data analysis and evidence from an in vitro study.Int J Colorectal Dis.2008;23(12):1223–


[22] Chang SC, Lin PC, Yang SH, et al. Mitochondrial D-loop mutation is a common event in colorectal cancers with p53 mutations.

Int J Colorectal Dis. 2009; 24(6): 623– 628.

[23] Xie H, Lev D, Gong Y, et al.Reduced mitochondrial DNA copy number in peripheral blood leukocytes increases the risk of soft

tissue sarcoma. Carcinogenesis. 2013; 34(5): 1039–1043.

[24] He Y, Gong Y, Gu J, Lee JJ, Lippman SM, Wu X.Increased leukocyte mitochondrial DNA copy number is associated with oral

premalignant lesions: an epidemiology study. Carcinogenesis. 2014; 35(8):1760-1764.

[25] Qu F, Liu X, Zhou F, et al.Association between mitochondrial DNA content in leukocytes and colorectal cancer risk: A case-control analysis. Cancer. 2011; 117(14): 3148–3155.

[26] Thyagarajan B, Wang R, Barcelo H, Koh WP, Yuan JM.Mitochondrial Copy Number is Associated with Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev.2012;21(9):1574–1581.

[27] Wang C, Zhao S, Du Y, Guo Z.Single nucleotide polymorphisms in the D-loop region of mitochondrial DNA is associated with

colorectal cancer outcome. Mitochondrial DNA A DNA Mapp Seq Anal.2016 Nov;27(6):4361-4363.

[28] Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010 Jun; 138(6):2059-72.

[29] Akbari M, Sykora P, Bohr VA.Slow mitochondrial repair of 5’-AMP renders mtDNA susceptible to damage in APTX deficient

cells.Sci Rep.2015 Aug 10;5:12876.

[30] Thyagarajan B, Guan W, Fedirko V, Barcelo H, Tu H, Gross M, Goodman M, Bostick RM.No association between mitochondrial

DNA copy number and colorectal adenomas.Mol Carcinog.2016 Aug;55(8):1290-6.

[31] Gao J, Wen S, Zhou H, Feng S (2015) De-methylation of displacement loop of mitochondrial DNA is associated with increased

mitochondrial copy number and nicotinamide adenine dinucleotide subunit 2 expression in colorectal cancer.Mol Med Rep 12(5):7033–7038

[32] Linkowska K, Jawień A, Marszałek A, et al. Mitochondrial DNA Polymerase γ Mutations and Their Implications in mtDNA Alterations in Colorectal Cancer.Ann Hum Genet.2015 Sep;79(5):320-328.

[33] Tipirisetti NR, Govatati S, Pullari P, et al. Mitochondrial control region alterations and breast cancer risk: a study in South Indian

population. PLoS One. 2014 Jan 30; 9(1):e85363.

[34] Wang C, Zhao S, Du Y, Guo Z (2016) Single nucleotide polymorphisms in the D-loop region of mitochondrial DNA is associated

with colorectal cancer outcome.Mitochondrial DNA A DNA Mapp Seq Anal 27(6):4361–4363.

[35] Venderbosch S, Van Vliet S, Craenmehr MH, Simmer F, de Haan AF, Punt CJ, Koopman M, Nagtegaal ID (2015) Mitochondrial

microsatellite instability in patients with metastatic colorectal cancer.Virchows Arch 466(5):495–502.

[36] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM.Estimates of worldwide burden of cancer in 2008: GLOBOCAN

2008. Int J Cancer. 2010; 127: 2893–2917.

[37] Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012; 379:1245 –1255.

[38] World Health Organisation (WHO) Databank. WHO statistical information system[Internet]. Geneva: WHO.

[39] Hsu CC, Lee HC, Wei YH.Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma.World J Gastroenterol. 2013; 19(47): 8880-8886.

[40] Yamada S, Nomoto S, Fujii T, Kaneko T, Takeda S, Inoue S, Kanazumi N, Nakao A. Correlation between copy number of mitochondrial DNA and clinico-pathologic parameters of hepatocellular carcinoma.Eur J Surg Oncol. 2006; 32:303–307.

[41] Yin PH, Wu CC, Lin JC, et al. Somatic mutations of mitochondrial genome in hepatocellular carcinoma.Mitochondrion.2010;10:174–182.

[42] McMahon S, LaFramboise T. Mutational patterns in the breast cancer mitochondrial genome, with clinical correlates. Carcinogenesis. 2014; 35: 1046–54.

[43] Hollestelle A, Peeters JK, Smid M, et al. Loss of E-cadherin is not a necessity for epithelial to mesenchymal transition in human

breast cancer.Breast Cancer Res Treat. 2013;138:47–57.

[44] Naito A, Cook CC, Mizumachi T, et al. Progressive tumor features accompany epithelial-mesenchymal transition induced in mitochondrial DNA-depleted cells. Cancer Sci. 2008; 99: 1584–8.

[45] Guha M, Srinivasan S, Ruthel G, et al. Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells. Oncogene.2014;33:5238–50.

[46] Thiery JP. Epithelial-mesenchymal transitions in tumour progression.Nat Rev Cancer. 2002; 2:442–54.

[47] Ebrahimi E, Almasi-Hashiani A, Ghaffari K, Shirkoohi R. Mitochondrial DNA copy number instability in ERBB2-amplified breast cancer tumors. EXCLI J. 2018; 17: 149-158.

[48] Weerts MJA, Sleijfer S, Martens JWM.The role of mitochondrial DNA in breast tumors.Drug Discov Today.2019 May;24(5):1202-1208.

Review Article