Advertisement

Potential Mechanisms of Mitochondrial DNA Mediated Acquired Mitochondrial Disease

  • Afshan N. Malik
  • Hannah S. Rosa
Chapter
First Online:

Abstract

Mitochondria are cellular organelles which contain mitochondrial DNA (MtDNA) in the form of an extranuclear genome. MtDNA can be present in 100s to thousands to copies per cell in the body depending on the bioenergetic requirements of the host cell. MtDNA encodes subunits of the electron transport chain and therefore is required to produce cellular energy in the form of ATP. However, MtDNA can also act as an inflammatory molecule since it resembles bacterial DNA, resulting in activation of pathways leading to enhanced cytokine production and chronic inflammation. In the current chapter, we suggest that MtDNA mediated mechanisms that cause systemic mitochondrial dysfunction are involved in many common diseases not traditionally recognised as mitochondrial disease, and we suggest that such disorders could be considered as “acquired mitochondrial diseases”, distinct from primary and secondary mitochondrial disease. Acquired mitochondrial diseases include cardiovascular and neurodegenerative disease as well as diabetic complications, and are associated with oxidative stress and sterile/chronic inflammation in their pathophysiology. We propose a mechanism of how systemic damage to MtDNA, mediated through oxidative stress, can cause inflammation and bioenergetic deficit. Some recent evidence of the proposed mechanism is provided for diabetic nephropathy, a complication of diabetes, which has not traditionally been regarded as a disease of mitochondrial dysfunction. According to the hypothesis proposed, it may be possible to use MtDNA levels in body fluids or cells to predict risk of acquired diseases of mitochondrial dysfunction, and to design novel therapies targeting the specific MtDNA mediated pathways.

Keywords

Mitochondrial DNA Mitochondrial dysfunction Acquired disease Metabolism Biomarker MtDNA Acquired mitochondrial disease Inflammation Oxidative stress 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

Thanks to Dr. Anna Czajka for donating Fig. 4. HSR is supported by an EFSD grant.

References

  1. Anderson S, Bankier AT, Barrell BG, De Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465CrossRefPubMedGoogle Scholar
  2. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147CrossRefPubMedGoogle Scholar
  3. Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson's disease. J Neurochem 139(Suppl 1):216–231CrossRefPubMedGoogle Scholar
  4. Boveris A, Oshino N, Chance B (1972) The cellular production of hydrogen peroxide. Biochem J 128:617–630CrossRefPubMedPubMedCentralGoogle Scholar
  5. Boyapati R, Tamborska A, Dorward D, Ho G (2017) Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases [version 1; referees: 3 approved]. F1000Res 6(F1000 Faculty Rev):169.  https://doi.org/10.12688/f1000research.10397.1 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brown TA, Tkachuk AN, Shtengel G, Kopek BG, Bogenhagen DF, Hess HF, Clayton DA (2011) Superresolution fluorescence imaging of mitochondrial nucleoids reveals their spatial range, limits, and membrane interaction. Mol Cell Biol 31:4994–5010CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cartoni R, Martinou J-C (2009) Role of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A. Exp Neurol 218:268–273CrossRefPubMedGoogle Scholar
  8. Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826–837CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chen N, Wen S, Sun X, Fang Q, Huang L, Liu S, Li W, Qiu M (2016) Elevated mitochondrial DNA copy number in peripheral blood and tissue predict the opposite outcome of cancer: a meta-analysis. Sci Rep 6:37404CrossRefPubMedPubMedCentralGoogle Scholar
  10. Croteau DL, Bohr VA (1997) Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J Biol Chem 272:25409–25412CrossRefPubMedGoogle Scholar
  11. Czajka A, Malik AN (2016) Hyperglycemia induced damage to mitochondrial respiration in renal mesangial and tubular cells: implications for diabetic nephropathy. Redox Biol 10:100–107CrossRefPubMedPubMedCentralGoogle Scholar
  12. Czajka A, Ajaz S, Gnudi L, Parsade CK, Jones P, Reid F, Malik AN (2015) Altered mitochondrial function, mitochondrial DNA and reduced metabolic flexibility in patients with diabetic nephropathy. EBioMedicine 2:499–512CrossRefPubMedPubMedCentralGoogle Scholar
  13. D’aco KE, Manno M, Clarke C, Ganesh J, Meyers KEC, Sondheimer N (2013) Mitochondrial tRNAPhe mutation as a cause of end-stage renal disease in childhood. Pediatr Nephrol 28:515–519CrossRefPubMedGoogle Scholar
  14. D'Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824CrossRefPubMedGoogle Scholar
  15. Donate-Correa J, Martin-Nunez E, Muros-de-Fuentes M, Mora-Fernandez C, Navarro-Gonzalez JF (2015) Inflammatory cytokines in diabetic nephropathy. J Diabetes Res 2015:9CrossRefGoogle Scholar
  16. Gardner K, Hall PA, Chinnery PF, Payne BA (2014) HIV treatment and associated mitochondrial pathology: review of 25 years of in vitro, animal, and human studies. Toxicol Pathol 42:811–822CrossRefPubMedGoogle Scholar
  17. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070CrossRefPubMedPubMedCentralGoogle Scholar
  18. Giles RE, Blanc H, Cann HM, Wallace DC (1980) Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A 77:6715–6719CrossRefPubMedPubMedCentralGoogle Scholar
  19. Gilkerson R, Bravo L, Garcia I, Gaytan N, Herrera A, Maldonado A, Quintanilla B (2013) The mitochondrial nucleoid: integrating mitochondrial DNA into cellular homeostasis. Cold Spring Harb Perspect Biol 5:a011080CrossRefPubMedPubMedCentralGoogle Scholar
  20. González-Cabo P, Palau F (2013) Mitochondrial pathophysiology in Friedreich's ataxia. J Neurochem 126:53–64CrossRefPubMedGoogle Scholar
  21. Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, Mcfarland R (2015) Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 77:753–759CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gorman GS, Chinnery PF, Dimauro S, Hirano M, Koga Y, McFarland R, Suomalainen A, Thorburn DR, Zeviani M, Turnbull DM (2016) Mitochondrial diseases. Nat Rev Dis Primers 2:16080CrossRefPubMedGoogle Scholar
  23. Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, OxfordGoogle Scholar
  24. Higgins GC, Coughlan MT (2014) Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br J Pharmacol 171:1917–1942CrossRefPubMedPubMedCentralGoogle Scholar
  25. Kasamatsu H, Robberson DL, Vinograd J (1971) A novel closed-circular mitochondrial DNA with properties of a replicating intermediate. Proc Natl Acad Sci U S A 68:2252–2257CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kukat C, Wurm CA, Spahr H, Falkenberg M, Larsson NG, Jakobs S (2011) Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc Natl Acad Sci U S A 108:13534–13539CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lightowlers RN, Chinnery PF, Turnbull DM, Howell N (1997) Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet 13:450–455CrossRefPubMedGoogle Scholar
  29. Luo S-M, Schatten H, Sun Q-Y (2013) Sperm mitochondria in reproduction: good or bad and where do they go? J Genet Genomics 40:549–556CrossRefPubMedGoogle Scholar
  30. Malik AN (2017) Mitochondrial DNA as a potential translational biomarker of mitochondrial dysfunction in drug induced toxicity studies. In: Dykens JA, Wills Y (eds) Drug induced mitochondrial dysfunction: progress towards the clinic. John Wiley & Sons Inc., New JerseyGoogle Scholar
  31. Malik AN, Czajka A (2013) Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13:481–492CrossRefPubMedGoogle Scholar
  32. Malik AN, Parsade CK, Ajaz S, Crosby-Nwaobi R, Gnudi L, Czajka A, Sivaprasad S (2015) Altered circulating mitochondrial DNA and increased inflammation in patients with diabetic retinopathy. Diabetes Res Clin Pract 110:257–265CrossRefPubMedGoogle Scholar
  33. Malik AN, Czajka A, Cunningham P (2016) Accurate quantification of mouse mitochondrial DNA without co-amplification of nuclear mitochondrial insertion sequences. Mitochondrion 29:59–64CrossRefPubMedGoogle Scholar
  34. Mazzaccara C, Iafusco D, Liguori R, Ferrigno M, Galderisi A, Vitale D, Simonelli F, Landolfo P, Prisco F, Masullo M, Sacchetti L (2012) Mitochondrial diabetes in children: seek and you will find it. PLoS One 7:e34956CrossRefPubMedPubMedCentralGoogle Scholar
  35. McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC, Matsumoto T, Webb RC (2015) Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res 107:119–130CrossRefPubMedPubMedCentralGoogle Scholar
  36. McClave SA, Snider HL (2001) Dissecting the energy needs of the body. Curr Opin Clin Nutr Metab Care 4:143–147CrossRefPubMedGoogle Scholar
  37. Mehta R, Chan K, Lee O, Tafazoli S, O'brien PJ (2008) Drug-associated mitochondrial toxicity. In: Dykens JA, Will Y (eds) Drug induced mitochondrial dysfunction. John Wiley & Sons, Inc., Hoboken, NJGoogle Scholar
  38. Michel S, Wanet A, De Pauw A, Rommelaere G, Arnould T, Renard P (2012) Crosstalk between mitochondrial (dys)function and mitochondrial abundance. J Cell Physiol 227:2297–2310CrossRefPubMedGoogle Scholar
  39. Miller FJ, Rosenfeldt FL, Zhang C, Linnane AW, Nagley P (2003) Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age. Nucleic Acids Res 31:e61–e61CrossRefPubMedPubMedCentralGoogle Scholar
  40. Morrow RM, Picard M, Derbeneva O, Leipzig J, McManus MJ, Gouspillou G, Barbat-Artigas S, dos Santos C, Hepple RT, Murdock DG, Wallace DC (2017) Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity. Proc Natl Acad Sci 114:2705–2710CrossRefPubMedPubMedCentralGoogle Scholar
  41. Murphy E, Ardehali H, Balaban RS, Dilisa F, Dorn GW 2nd, Kitsis RN, Otsu K, Ping P, Rizzuto R, Sack MN, Wallace D, Youle RJ (2016) Mitochondrial function, biology, and role in disease: a scientific statement from the American heart association. Circ Res 118:1960–1991CrossRefPubMedGoogle Scholar
  42. Nakahira K, Kyung S-Y, Rogers AJ, Gazourian L, Youn S, Massaro AF, Quintana C, Osorio JC, Wang Z, Zhao Y, Lawler LA, Christie JD, Meyer NJ, Causland FRM, Waikar SS, Waxman AB, Chung RT, Bueno R, Rosas IO, Fredenburgh LE, Baron RM, Christiani DC, Hunninghake GM, Choi AMK (2014) Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med 10:e1001577CrossRefGoogle Scholar
  43. Newsholme P, Haber EP, Hirabara SM, Rebelato EL, Procopio J, Morgan D, Oliveira-Emilio HC, Carpinelli AR, Curi R (2007) Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. J Physiol 583:9–24CrossRefPubMedPubMedCentralGoogle Scholar
  44. Niyazov DM, Kahler SG, Frye RE (2016) Primary mitochondrial disease and secondary mitochondrial dysfunction: importance of distinction for diagnosis and treatment. Mol Syndromol 7:122–137CrossRefPubMedPubMedCentralGoogle Scholar
  45. Nordberg J, Arnér ESJ (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system1 1This review is based on the licentiate thesis “Thioredoxin reductase—interactions with the redox active compounds 1-chloro-2,4-dinitrobenzene and lipoic acid” by Jonas Nordberg, 2001, Karolinska Institute, Stockholm, ISBN 91-631-1064-4. Free Radic Biol Med 31:1287–1312CrossRefPubMedGoogle Scholar
  46. Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K (2012) Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485:251–255CrossRefPubMedPubMedCentralGoogle Scholar
  47. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong S-E, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123CrossRefPubMedPubMedCentralGoogle Scholar
  48. Picard M, Wallace DC, Burelle Y (2016) The rise of mitochondria in medicine. Mitochondrion 30:105–116CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rydstrom J (2006) Mitochondrial NADPH, transhydrogenase and disease. Biochim Biophys Acta 1757:721–726CrossRefPubMedGoogle Scholar
  50. Schon EA, Dimauro S, Hirano M (2012) Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 13:878–890CrossRefPubMedPubMedCentralGoogle Scholar
  51. Schwartz M, Vissing J (2002) Paternal inheritance of mitochondrial DNA. N Engl J Med 347:576–580CrossRefPubMedGoogle Scholar
  52. Seidowsky A, Hoffmann M, Glowacki F, Dhaenens CM, Devaux JP, de Sainte Foy CL, Provot F, Gheerbrant JD, Hummel A, Hazzan M, Dracon M, Dieux-Coeslier A, Copin MC, Noel C, Buob D (2013) Renal involvement in MELAS syndrome–a series of 5 cases and review of the literature. Clin Nephrol 80:456–463CrossRefPubMedGoogle Scholar
  53. Selak MA, Lyver E, Micklow E, Deutsch EC, Önder Ö, Selamoglu N, Yager C, Knight S, Carroll M, Daldal F, Dancis A, Lynch DR, Sarry J-E (2011) Blood cells from Friedreich ataxia patients harbor frataxin deficiency without a loss of mitochondrial function. Mitochondrion 11:342–350CrossRefPubMedGoogle Scholar
  54. Semeraro F, Cancarini A, Dell’omo R, Rezzola S, Romano MR, Costagliola C (2015) Diabetic retinopathy: vascular and inflammatory disease. J Diabetes Res 2015:16CrossRefGoogle Scholar
  55. Shadel GS, Clayton DA (1997) Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem 66:409–435CrossRefPubMedGoogle Scholar
  56. Shoubridge EA, Wai T (2007) Mitochondrial DNA and the mammalian oocyte. Curr Top Dev Biol 77:87–111CrossRefPubMedGoogle Scholar
  57. Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6:389–402CrossRefPubMedPubMedCentralGoogle Scholar
  58. Trinei M, Berniakovich I, Pelicci PG, Giorgio M (2006) Mitochondrial DNA copy number is regulated by cellular proliferation: a role for Ras and p66Shc. Biochim Biophys Acta 1757:624–630CrossRefPubMedGoogle Scholar
  59. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488CrossRefPubMedGoogle Scholar
  60. Wang Z, Ying Z, Bosy-Westphal A, Zhang J, Schautz B, Later W, Heymsfield SB, Müller MJ (2010) Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr 92:1369–1377CrossRefPubMedPubMedCentralGoogle Scholar
  61. Welsh P, Grassia G, Botha S, Sattar N, Maffia P (2017) Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect? Br J Pharmacol 174(22):3898–3913CrossRefPubMedPubMedCentralGoogle Scholar
  62. Wilkins HM, Swerdlow RH (2016) Relationships between mitochondria and neuroinflammation: implications for Alzheimer's disease. Curr Top Med Chem 16:849–857CrossRefPubMedPubMedCentralGoogle Scholar
  63. Wu F, Wang J, Pu C, Qiao L, Jiang C (2015) Wilson's disease: a comprehensive review of the molecular mechanisms. Int J Mol Sci 16:6419–6431CrossRefPubMedPubMedCentralGoogle Scholar
  64. Walker UA. Lipoatrophy and Other Manifestations of antiretroviral therapeutics. In: J.A. D, Will Y, editors. Drug Induced Mitochondrial Dysfunction Hoboken, NJ, USA; 2008Google Scholar
  65. Yamanouchi S, Kudo D, Yamada M, Miyagawa N, Furukawa H, Kushimoto S (2013) Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: time course and the association with clinical status. J Crit Care 28:1027–1031CrossRefPubMedGoogle Scholar
  66. Ying W (2008) NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal 10:179–206CrossRefPubMedGoogle Scholar
  67. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–107CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Diabetes Research Group, Faculty of Life Sciences and MedicineKing’s College LondonLondonUK

Personalised recommendations

Cite chapter

Buy options