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Mini Review - (2016) Volume 7, Issue 2

The Cell-Free Mitochondrial DNA: A Novel Biomarker of Cardiovascular Risk?

Alexander E Berezin*

Internal Medicine Department, State Medical University of Zaporozhye, Ukraine

*Corresponding Author:
Alexander E Berezin, Professor, MD, PhD
Consultant of Therapeutic Unit, Internal Medicine Department, State Medical University of Zaporozhye, 26, Mayakovskyav, Zaporozhye, UA-69035, Ukraine
Tel: +380612894585
E-mail: [email protected]; [email protected]

Received date: May 15, 2016; Accepted date: May 25, 2016; Published date: May 30, 2016

Citation: Berezin AE. The Cell-Free Mitochondrial DNA: A Novel Biomarker of Cardiovascular Risk? Transl Biomed. 2016, 7: 2.

Visit for more related articles at Translational Biomedicine

Abstract

Circulating cell-free mitochondrial DNA could find in healthy subjects and patients with neoplasia, trauma, infections, stroke, autoimmune, metabolic and rheumatic diseases. The triggers of cell-free mitochondrial DNA secretion are various impacts, i.e. microbial antigen stimulation, inflammatory cytokine, active molecules. It is speculated that the cell-free mitochondrial DNA might be a critical activator of inflammation, coagulation and the innate immune system linking mitochondrial dysfunction, cell death and target organ injury. There is evidence regarding that the cell-free mitochondrial DNA levels may elevate in healthy individuals depending aging and in cancer and non-cancer subjects at risk of CV diseases, as well as in persons with established CH disease. The results of several studies have shown that elevated circulating cell-free mitochondrial DNA has associated with cardiovascular (CV) diseases, while diagnostic and predictive value of this biomarker in non-cancer individuals is not fully clear. The mini review is devoted the biological role, diagnostic and predictive value of cellfree mitochondrial DNA in patients at CV risk.

Keywords

Cardiovascular disease; Endothelial dysfunction; Cell-free mitochondrial DNA; Clinical outcomes; Prediction

Introduction

The advances in the treatment of cardiovascular (CV) disease over last decades have leaded to decrease mortality and disability due to CV events in the developed countries [1]. However, the increased prevalence of CV disease associates with high economic burden and medical care expenditures. Data of recent clinical trials have been shown the improvement of survival of the patients after CV events might predict with biological markers reflecting the several phases of the pathogenesis of CV disease. Current clinical guidelines presented by American College of Cardiology/American Heart Association and European Society of Cardiology are emphasized needing to use biomarkers toward risk stratification of individuals at higher risk of CV disease, patients with known CV disease, as well as target therapy of several diseases (e.g. heart failure). The accuracy and predictive value of widely used biomarkers (i.e. cardiac troponins, natriuretic peptides, galectin-3, soluble ST2) are sufficiently distinguished depending age, sex, metabolic comorbidities, decreased kidney function. In this context, the discovery of novel biomarkers that might use to identify the individual CV risk is discussed widely.

Recent studies have revealed the increased concentration of nucleic acids defined as DNA (genomic DNA, mitochondrial DNA, viral DNA) and RNA (mRNA and microRNAs) in the circulation among patients with several diseases including CV and rheumatic diseases, diabetes, sepsis, infections [2,3]. Moreover, cell-free nucleic acids were measured in the circulation in healthy subjects and the concentration of the both cell-free DNA and RNA may depend on aging. Although the molecular mechanisms leading to release of nucleic acids from cells into circulation are yet not completely clear [4], it is suggested that apoptotic and/or necrotic cells could be defined as the main source of cell-free DNA and RNA [5]. Moreover, target cells may produce actively and secrete nucleic acid resulting in several triggers, such as microbial lipopolysaccharides/antigenes, tumor cells, inflammatory cytokines, active molecules [6-8], in two transferred forms, i.e. cell-free circulating fraction and microvesicle-derived fraction [9,10]. However, extracellular microvesicles may convey a small portion of the both DNA and RNA, whereas the majority of nucleic acids represent as free circulating form [11]. Because mitochondrial DNA are secreted by apoptotic and activated cells triggering CV risk factors [11-13], they have some theoretical advantages as CV biomarkers of genomic DNA released from necrotic cells and appear to be tumor biomarker. The mini review is devoted the biological role, diagnostic and predictive value of cell-free mitochondrial DNA in patients at CV risk.

Biological role of circulating cell-free mitochondrial DNA

Cell-free mitochondrial DNA appears to be found as doublestranded molecules, which are biologically fragmented into both short (lower than 1 Kb) and long (up to 21 kb) segments [14]. The spontaneously released mitochondrial DNA fraction has been shown to be present in both actively dividing and non-dividing forms. Moreover, secretion of mitochondrial DNA has associated with DNA-dependent RNA or DNA polymerase and may have a lower molecular weight than the typical genetic mitochondrial DNA fractions [15]. Interestingly, lower molecular weight mitochondrial DNA fraction might term metabolic DNA and represent the precursor to the formation of the spontaneously released DNA fraction [16]. The active secretion of mitochondrial DNA fractions needs to involving of antigen-presenting cells (i.e. mononuclears/macrophages, lymphocytes, dendritic cells) and regulating by hormonal mechanisms [17-19]. In this context, cell-free mitochondrial DNA content in contrast miRNAs could reflect a severity of cardiac damage and probably might have a predictive value in humans with acute myocardial infarction [20-22].

The biological role of cell-free mitochondrial DNA and its fragments is controversial. The controversy relates an ability of DNA fragments to impair both mitochondrial function and membrane cells, as well as to induce tissue reparation [23]. Indeed, recent studies have shown cell-free mitochondrial DNA may not only activate inflammation, coagulation and immunity through the toll-like receptor (TLR)-3 and TLR-9, but induce cell death and tissue damage. Finally, cell-free mitochondrial DNA is directly involved in the pathogenesis of endothelial dysfunction and vasculopathies, which are discussed an important component of development of CV diseases, rheumatic and autoimmune disease, malignancy [24-26]. On the other hand, cell-free mitochondrial DNA might contribute to endogenous repair systems through regulation of mobbing and differentiation of progenitor cells [24].

The cell free mitochondrial DNA in CV diseases

The association between concentration of mitochondrial DNA and CV risk was found in the numerous recent studies [26-28]. It is supposed that circulating fragments of cell-free mitochondrial DNA could be a trigger of development of early endothelial dysfunction and tissue injury among individuals at higher CV risk [23,29], patients with acute myocardial infarction after percutaneous coronary artery intervention [30].

There are the results of two prospective observational cohort studies devoted the discovery of predictive role of elevated cell-free mitochondrial DNA levels in the intensive care unit patients (the Brigham and Women's Hospital Registry of Critical Illness and Molecular Epidemiology of Acute Respiratory Distress Syndrome) [31]. It has found a markedly association between circulating levels of mitochondrial DNA and in-hospital mortality. However, it is needed to note that there is no evidence of large clinical trials to extrapolate the data to patient population with known CV disease.

Additionally, elevated cell-free mitochondrial DNA levels could be important challenge in the risk stratification of the subjects with asymptomatic atherosclerosis, acute coronary syndrome, myocardial infarction, heart failure, pulmonary thromboembolism [32-36]. There is a large body of evidence regarding the molecular alterations of cell-free mitochondrial DNA and its relationship with tumor development and progression [3]. Indeed, most of the molecular alterations found in cell-free mitochondrial DNA circulating in plasma reflect the genetic and epigenetic changes found in primary tumors. In this context, it is important to define that long cellfree mitochondrial DNA fragments relate to necrosis phenomena, whereas shorter fragments are produced by physiological apoptosis phenomena and in aging [37]. Probably, so-called integrity index, based on the ratio between long and short cell-free mitochondrial DNA fragments, might useful in patients with cancers [38].

Interestingly the clinical use of cell-free mitochondrial DNA measurement is limited by several technical obstacles associated with undefined reproducibility of the serial measurement [39]. However, the single-measured cell-free mitochondrial DNA level has used with diagnostic value in persons suspected cancers [40,41]. Finally, the use of continuing biomarker monitoring of cell-free DNAs has been questioned. It relates to sufficient overlapping circulating levels of cell-free DNA in healthy individuals and patients with underlying diseases including tumor, CV disease, infections, and inflammation. The decreased levels of cell-free DNA were found in cancer survivors after completed surgical care or chemo/radiotherapy. Additionally, patients who exhibited high levels of cell-free DNA might have a high risk of relapse or are considered not responders to the treatment. Whether measurement of circulating variabilities of cell-free DNA could help to stratify non-cancer patients at CV risk is not clear, while the acute myocardial infarction patients after percutaneous coronary intervention/successful thrombolysis or cardiopulmonary resuscitation might demonstrate tendency to decrease of concentration [31,33,34,42]. Furthermore, there is a closely association between cell-free DNA with hospital mortality and organ dysfunction [43,44]. All these require more investigations to confirm the role of cell-free mitochondrial DNA in CV diseases.

Conclusion

Cell-free mitochondrial DNA levels may elevate in healthy individuals depending aging and in cancer and non-cancer subjects at risk of CV diseases, as well as in persons with established CH disease. The measurement of fragments of cellfree mitochondrial DNA may be use in routine clinical practice as a useful biomarker of non-specific tissue damage with higher predictive value in non-cancer individuals with CV diseases.

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References

  1. Yusuf S, Rangarajan S, Teo K, Islam S, Li W, et al. (2014) Cardiovascular risk and events in 17 low-, middle-, and high-income countries. N Engl J Med 371: 818-827.
  2. Suzuki N, Kamataki A, Yamaki J, Homma Y (2008) Characterization of circulating DNA in healthy human plasma. Clin Chim Acta 387: 55-58.
  3. Gonzalez-Masia JA, Garcia OD, Garcia Olmo DC (2013) Circulating nucleic acids in plasma and serum (CNAPS): applications in oncology. Onco Targets Ther 6: 819-832.
  4. Muotri AR, Marchetto MC, Coufal NG, Gage FH (2007) The necessary junk: new functions for transposable elements. Hum Mol Genet 16: R159-R167.
  5. Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, et al. (2001) DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61: 1659-1665.
  6. Chen Z, Fadiel A, Naftolin F, Eichenbaum KD, Xia Y (2005) Circulation DNA: biological implications for cancer metastasis and immunology. Med Hypotheses 65: 956-961.
  7. Stroun M, Lyautey J, Lederrey C, Olson SA, Anker P (2001) About the possible origin and mechanism of circulating DNA: Apoptosis and active DNA release. Clin Chim Acta 313: 139-142.
  8. Stroun M, Maurice P, Vasioukhin V, Lyautey J, Lederrey C, et al. (2000) The origin and mechanism of circulating DNA. Ann NY Acad Sci 906: 161-168.
  9. Li Y, Zimmermann B, Rusterholz C, Kang A, Holzgreve W, et al. (2004) Size separation of circulatory DNA in maternal plasma permits ready detection of fetal DNA polymorphisms. Clin Chem 50: 1002-1011.
  10. van der Vaart M, Pretorius PJ (2007) The origin of circulating free DNA. Clin Chem 53: 2215.
  11. Helmig S, Fruhbeis C, Kramer-Albers EM, Simon P, Tug S (2015) Release of bulk cell free DNA during physical exercise occurs independent of extracellular vesicles. Eur J Appl Physiol.
  12. Berezin A (2016) Metabolic memory phenomenon in diabetes mellitus: Achieving and perspectives. Diabetes Metab Syndr.
  13. Berezin AE, Kremzer AA, Berezina TA, Martovitskaya YV (2016) The pattern of circulating microparticles in patients with diabetes mellitus with asymptomatic atherosclerosis. Acta Clin Belg 3:1-8.
  14. Chandrananda D, Thorne NP, Bahlo M (2015) High-resolution characterization of sequence signatures due to non-random cleavage of cell-free DNA. BMC Med Genomics 8: 29.
  15. Gahan PB, Anker P, Stroun M (2008) Metabolic DNA as the origin of spontaneously released DNA? Ann N Y Acad Sci 1137: 7-17.
  16. Pisetsky DS, Fairhurst AM (2007) The origin of extracellular DNA during the clearance of dead and dying cells. Autoimmunity 40: 281-284.
  17. Jiang N, Reich CF 3rd, Pisetsky DS (2003) Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells. Blood 102: 2243-2250.
  18. Pisetsky DS, Jiang N (2006) The generation of extracellular DNA in SLE: the role of death and sex. Scand J Immunol 64: 200-204.
  19. Choi JJ, Reich CF, Pisetsky DS (2005) The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells. Immunology 115: 55-62.
  20. Chen C, Xu J, Huang F (2013) Recent players in the field of acute myocardial infarction biomarkers: circulating cell-free DNA or microRNAs? Int J Cardiol 168: 2956-2657.
  21. Bliksoen M, Mariero LH, Ohm IK, Haugen F, Yndestad A, et al. (2012) Increased circulating mitochondrial DNA after myocardial infarction. Int J Cardiol 158: 132-134.
  22. Andreyev AY, Kushnareva YE, Murphy AN, Starkov AA (2015) Mitochondrial ROS Metabolism: 10 Years Later. Biochemistry (Mosc) 80: 517-531.
  23. Alvarado VN (2015) Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient. Exp Gerontol 69: 70-8.
  24. Malik AN, Czajka A (2013) Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13: 481-492.
  25. Bhagirath VC, Dwivedi DJ, Liaw PC (2015) Comparison of the Proinflammatory and Procoagulant Properties of Nuclear, Mitochondrial, and Bacterial DNA. Shock 44: 265-271.
  26. Surmiak MP, Hubalewska MM, Wawrzycka AK, Szczeklik W, Musial J, et al. (2015) Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis. Clin Exp Immunol 181: 150-155.
  27. Jiang P, Chan CW, Chan KC, Cheng SH, Wong J, et al. (2015) Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci USA 112: E1317-E1325.
  28. Chen S, Xie X, Wang Y, Gao Y, Xie X, et al. (2014) Association between leukocyte mitochondrial DNA content and risk of coronary heart disease: a case-control study. Atherosclerosis 237: 220-226.
  29. Liu J, Cai X, Xie L, Tang Y, Cheng J, et al. (2015) Circulating Cell Free Mitochondrial DNA is a Biomarker in the Development of Coronary Heart Disease in the Patients with Type 2 Diabetes. Clin Lab 61: 661-667.
  30. Borghini A, Mercuri A, Turchi S, Chiesa MR, Piccaluga E, et al. (2015) Increased circulating cell-free DNA levels and mtDNA fragments in interventional cardiologists occupationally exposed to low levels of ionizing radiation. Environ Mol Mutagen 56: 293-300.
  31. Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, et al. (2013) Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med 10: e1001577.
  32. Cerne D, Bajalo JL (2014) Cell-free nucleic acids as a non-invasive route for investigating atherosclerosis. Curr Pharm Des 20: 5004-5009.
  33. Arnalich F, Maldifassi MC, Ciria E, Codoceo R, Renart J, et al. (2013) Plasma levels of mitochondrial and nuclear DNA in patients with massive pulmonary embolism in the emergency department: a prospective cohort study. Crit Care 17: R90.
  34. Yellow DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 17: 1121-1135.
  35. Neto Neves EM (2013) Cell-free DNA as a promising marker for risk stratification of pulmonary embolism. Crit Care 17: 464.
  36. Uzuelli JA, Dias-Junior CA, Izidoro-Toledo TC, Gerlach RF, Tanus-Santos JE (2009) Circulating cell-free DNA levels in plasma increase with severity in experimental acute pulmonary thromboembolism. Clin Chim Acta 17: 112-116.
  37. Fournie GJ, Martres F, Porrat JP, Alary C, Rumeau M (1993)Plasma DNA as cell death marker in elderly patients. Gerontology 39: 215-221.
  38. Gormally E, Caboux E, Vineis P, Hainaut P (2007) Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. Mutat Res 635: 105-117.
  39. Vaart M van der, Pretorius PJ (2008) Circulating DNA. Its origin and fluctuation. Ann NY Acad Sci 1137: 18-26.
  40. Frank MO (2016) Circulating Cell-Free DNA Differentiates Severity of Inflammation. Biol Res Nurs pii: 1099800416642571.
  41. Qin Z, Ljubimov VA, Zhou C, Tong Y, Liang J (2016) Cell-free circulating tumor DNA in cancer. Chin J Cancer 35: 36.
  42. Adrie C, Adib CM, Laurent I,Monchi M, Vinsonneau C, et al. (2002) Successful cardiopulmonary resus citation after cardiac arrest as a "sepsis-like" syndrome. Circulation 106: 562-568.
  43. Saukkonen K, Lakkisto P, Varpula M, Varpula T, Voipio-Pulkki LM, et al. (2007) Association of cell-free plasma DNA with hospital mortality and organ dysfunction in intensive care patients. Intensive Care Med 33: 1624-1627.
  44. Rhodes A, Wort SJ, Thomas H, Collinson P, Bennett ED (2006) Plasma DNAconcentration as predictor of mortality and sepsis in critically ill patients. Crit Care 10: R60.