Open Access

Mitochondrial DNA heteroplasmy in human health and disease (Review)

  • Authors:
    • George B. Stefano
    • Richard M. Kream
  • View Affiliations

  • Published online on: February 4, 2016     https://doi.org/10.3892/br.2016.590
  • Pages: 259-262
  • Copyright: © Stefano et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The biomedical literature has extensively documented the functional roles of genetic polymorphisms in concert with well‑characterized somatic mutations in the etiology and progression of major metastatic diseases afflicting human populations. Mitochondrial heteroplasmy exists as a dynamically determined co‑expression of inherited polymorphisms and somatic mutations in varying ratios within individual mitochondrial DNA genomes with repetitive patterns of tissue specificity. Mechanistically, carcinogenic cellular processes include profound alterations of normative mitochondrial function, notably dependence on aerobic and anaerobic glycolysis, and aberrant production and release of lactate, according to a classic theory. Within the translational context of human health and disease, the present review discusses the necessity of establishing critical foci designed to probe multiple biological roles of mitochondrial heteroplasmy in cancer biology.

References

1 

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr and Kinzler KW: Cancer genome landscapes. Science. 339:1546–1558. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Frank SA: Somatic mosaicism and disease. Curr Biol. 24:R577–R581. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, Boin F, Fava A, Thoburn C, Kinde I, et al: Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science. 343:152–157. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Ross KA: Coherent somatic mutation in autoimmune disease. PLoS One. 9:e1010932014. View Article : Google Scholar : PubMed/NCBI

5 

Poduri A, Evrony GD, Cai X and Walsh CA: Somatic mutation, genomic variation, and neurological disease. Science. 341:12377582013. View Article : Google Scholar : PubMed/NCBI

6 

Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, et al: Somatic mutations in cerebral cortical malformations. N Engl J Med. 371:733–743. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Taylor RW and Turnbull DM: Mitochondrial DNA mutations in human disease. Nat Rev Genet. 6:389–402. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Song S, Pursell ZF, Copeland WC, Longley MJ, Kunkel TA and Mathews CK: DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. Proc Natl Acad Sci USA. 102:4990–4995. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Crimi M, O'Hearn SF, Wallace DC and Comi GP: Molecular research technologies in mitochondrial diseases: The microarray approach. IUBMB Life. 57:811–818. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Wallace DC: The mitochondrial genome in human adaptive radiation and disease: On the road to therapeutics and performance enhancement. Gene. 354:169–180. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Kenney MC, Chwa M, Atilano SR, Falatoonzadeh P, Ramirez C, Malik D, Tarek M, Cáceres-del-Carpio J, Nesburn AB, Boyer DS, et al: Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: Insights into mitochondrial-nuclear interactions. Hum Mol Genet. 23:3537–3551. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Kenney MC, Chwa M, Atilano SR, Falatoonzadeh P, Ramirez C, Malik D, Tarek M, Del Carpio JC, Nesburn AB, Boyer DS, et al: Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: Implications for population susceptibility to diseases. Biochim Biophys Acta. 1842:208–219. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Atilano SR, Malik D, Chwa M, et al: Mitochondrial DNA variants can mediate methylation status of inflammation, angiogenesis and signaling genes. Hum Mol Genet. 24:4491–4503. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Bera S, Weinberg F, Ekoue DN, Ansenberger-Fricano K, Mao M, Bonini MG and Diamond AM: Natural allelic variations in glutathione peroxidase-1 affect its subcellular localization and function. Cancer Res. 74:5118–5126. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Liu M, Li Y, Chen L, Chan TH, Song Y, Fu L, Zeng TT, Dai YD, Zhu YH, Li Y, et al: Allele-specific imbalance of oxidative stress-induced growth inhibitor 1 associates with progression of hepatocellular carcinoma. Gastroenterology. 146:1084–1096. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, et al: Sequence and organization of the human mitochondrial genome. Nature. 290:457–465. 1981. View Article : Google Scholar : PubMed/NCBI

17 

Valero T: Mitochondrial biogenesis: Pharmacological approaches. Curr Pharm Des. 20:5507–5509. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Irwin JA, Saunier JL, Niederstätter H, Strouss KM, Sturk KA, Diegoli TM, Brandstätter A, Parson W and Parsons TJ: Investigation of heteroplasmy in the human mitochondrial DNA control region: A synthesis of observations from more than 5000 global population samples. J Mol Evol. 68:516–527. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Jayaprakash AD, Benson EK, Gone S, Liang R, Shim J, Lambertini L, Toloue MM, Wigler M, Aaronson SA and Sachidanandam R: Stable heteroplasmy at the single-cell level is facilitated by intercellular exchange of mtDNA. Nucleic Acids Res. 43:2177–2187. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Naue J, Hörer S, Sänger T, Strobl C, Hatzer-Grubwieser P, Parson W and Lutz-Bonengel S: Evidence for frequent and tissue-specific sequence heteroplasmy in human mitochondrial DNA. Mitochondrion. 20:82–94. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Schon EA and Gilkerson RW: Functional complementation of mitochondrial DNAs: Mobilizing mitochondrial genetics against dysfunction. Biochim Biophys Acta. 1800:245–249. 2010. View Article : Google Scholar : PubMed/NCBI

22 

He Y, Wu J, Dressman DC, Iacobuzio-Donahue C, Markowitz SD, Velculescu VE, Diaz LA Jr, Kinzler KW, Vogelstein B and Papadopoulos N: Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature. 464:610–614. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Samuels DC, Li C, Li B, Song Z, Torstenson E, Clay Boyd H, Rokas A, Thornton-Wells TA, Moore JH, Hughes TM, et al: Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet. 9:e10039292013. View Article : Google Scholar : PubMed/NCBI

24 

Chen Z, Qi Y, French S, Zhang G, Garcia Covian R, Balaban R and Xu H: Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function. Mol Biol Cell. 26:674–684. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Hill JH, Chen Z and Xu H: Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant. Nat Genet. 46:389–392. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, et al: Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 514:628–632. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Berridge MV, Dong L and Neuzil J: Mitochondrial DNA in Tumor Initiation, Progression, and Metastasis: Role of Horizontal mtDNA Transfer. Cancer Res. 75:3203–3208. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Stefano GB, Mantione KJ, Casares FM and Kream RM: Anaerobically functioning mitochondria: Evolutionary perspective on modulation of energy metabolism in Mytilus edulis. Invertebrate Surviv J. 12:22–28. 2015.

29 

Stefano GB, Snyder C and Kream RM: Mitochondria, chloroplasts in animal and plant cells: Significance of conformational matching. Med Sci Monit. 21:2073–2078. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Warburg O, Gawehn K, Geissler AW, Kayser D and Lorenz S: Experiments on anaerobiosis of cancer cells. Klin Wochenschr. 43:289–293. 1965.(In German). View Article : Google Scholar : PubMed/NCBI

31 

Seyfried TN: Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol. 3:432015. View Article : Google Scholar : PubMed/NCBI

32 

Seyfried TN, Flores R, Poff AM, D'Agostino DP and Mukherjee P: Metabolic therapy: A new paradigm for managing malignant brain cancer. Cancer Lett. 356(2 Pt A): 289–300. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Stefano GB and Kream RM: Cancer: Mitochondrial origins. Med Sci Monit. 21:3736–3739. 2015.PubMed/NCBI

34 

Snyder C, Kream RM, Ptacek R and Stefano GB: Mitochondria, microbiome and their potential psychiatric modulation. Autism Open Access. 5:1442015. View Article : Google Scholar

35 

Fujimura KE, Slusher NA, Cabana MD and Lynch SV: Role of the gut microbiota in defining human health. Expert Rev Anti Infect Ther. 8:435–454. 2010. View Article : Google Scholar : PubMed/NCBI

36 

Guinane CM and Cotter PD: Role of the gut microbiota in health and chronic gastrointestinal disease: Understanding a hidden metabolic organ. Therap Adv Gastroenterol. 6:295–308. 2013. View Article : Google Scholar : PubMed/NCBI

37 

Greaves LC, Reeve AK, Taylor RW and Turnbull DM: Mitochondrial DNA and disease. J Pathol. 226:274–286. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Li M, Schröder R, Ni S, Madea B and Stoneking M: Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations. Proc Natl Acad Sci USA. 112:2491–2496. 2015. View Article : Google Scholar : PubMed/NCBI

39 

Goto H, Dickins B, Afgan E, Paul IM, Taylor J, Makova KD and Nekrutenko A: Dynamics of mitochondrial heteroplasmy in three families investigated via a repeatable re-sequencing study. Genome Biol. 12:R592011. View Article : Google Scholar : PubMed/NCBI

40 

Allen JF: Why chloroplasts and mitochondria retain their own genomes and genetic systems: Colocation for redox regulation of gene expression. Proc Natl Acad Sci USA. 112:10231–10238. 2015. View Article : Google Scholar : PubMed/NCBI

41 

Xu X, Duan S, Yi F, Ocampo A, Liu GH and Belmonte Izpisua JC: Mitochondrial regulation in pluripotent stem cells. Cell Metab. 18:325–332. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Blümlein K, Wanker EE, Ralser M, Cramer T, et al: HIF1α modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells. 32:364–376. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Stefano GB and Kream RM: Hypoxia defined as a common culprit/initiation factor in mitochondrial-mediated proinflammatory processes. Med Sci Monit. 21:1478–1484. 2015. View Article : Google Scholar : PubMed/NCBI

44 

Campello S, Lacalle RA, Bettella M, Mañes S, Scorrano L and Viola A: Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J Exp Med. 203:2879–2886. 2006. View Article : Google Scholar : PubMed/NCBI

45 

Campello S and Scorrano L: Mitochondrial shape changes: Orchestrating cell pathophysiology. EMBO Rep. 11:678–684. 2010. View Article : Google Scholar : PubMed/NCBI

46 

Wallace DC: A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu Rev Genet. 39:359–407. 2005. View Article : Google Scholar : PubMed/NCBI

47 

Calloway CD, Reynolds RL, Herrin GL Jr and Anderson WW: The frequency of heteroplasmy in the HVII region of mtDNA differs across tissue types and increases with age. Am J Hum Genet. 66:1384–1397. 2000. View Article : Google Scholar : PubMed/NCBI

48 

Snyder C and Stefano GB: Mitochondria and chloroplasts shared in animal and plant tissues: Significance of communication. Med Sci Monit. 21:1507–1511. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

March 2016
Volume 4 Issue 3

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Stefano, G.B., & Stefano, G.B. (2016). Mitochondrial DNA heteroplasmy in human health and disease (Review). Biomedical Reports, 4, 259-262. https://doi.org/10.3892/br.2016.590
MLA
Stefano, G. B., Kream, R. M."Mitochondrial DNA heteroplasmy in human health and disease (Review)". Biomedical Reports 4.3 (2016): 259-262.
Chicago
Stefano, G. B., Kream, R. M."Mitochondrial DNA heteroplasmy in human health and disease (Review)". Biomedical Reports 4, no. 3 (2016): 259-262. https://doi.org/10.3892/br.2016.590