Increased mitochondrial common deletion in platelets from patients with type 2 diabetes is not associated with abnormal platelet activity or mitochondrial function

Karimova,Ayla; Hacioğlu,Yalçin; Bahtiyar,Nurten; Niyazoğlu,Mutlu; Akbaş,Fahri; Yilmaz,Erkan; Ulutin,Turgut; Onaran,Ilhan

doi:10.3892/mmr.2018.9340

Increased mitochondrial common deletion in platelets from patients with type 2 diabetes is not associated with abnormal platelet activity or mitochondrial function

Authors:
- Ayla Karimova
- Yalçin Hacioğlu
- Nurten Bahtiyar
- Mutlu Niyazoğlu
- Fahri Akbaş
- Erkan Yilmaz
- Turgut Ulutin
- Ilhan Onaran
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Affiliations: Department of Medical Biology and Genetics, Cerrahpasa Faculty of Medicine, Istanbul University, 34098 Istanbul, Turkey, Department of Family Medicine, Istanbul Training and Research Hospital, 34098 Istanbul, Turkey, Department of Biophysics, Cerrahpasa Faculty of Medicine, Istanbul University, 34098 Istanbul, Turkey, Department of Endocrinology, Istanbul Training and Research Hospital, 34098 Istanbul, Turkey, Department of Medical Biology, Faculty of Medicine at Bezmialem Vakif University, 34093 Istanbul, Turkey, Tissue Typing Laboratory, Cerrahpasa Faculty of Medicine, Istanbul University, 34098 Istanbul, Turkey
Published online on: July 31, 2018 https://doi.org/10.3892/mmr.2018.9340
Pages: 3529-3536

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Abstract

The present study examined the presence and frequency of the 4,977‑base pair mitochondrial (mt)DNA (mtDNA4977) deletion in blood platelets, and whether increased mtDNA4977 deletion was associated with abnormal mitochondrial and platelet function in type 2 diabetes mellitus. A total of 66 patients with type 2 diabetes mellitus and 23 healthy subjects were included in the present study. Patients were divided into three subgroups according to glycemic control, and the presence or absence of chronic diabetic complications: i) Good glycemic control [glycated hemoglobin (HbA1c) <7] without complications; ii) poor glycemic control (HbA1c ≥7) without complications; and iii) poor glycemic control (HbA1c ≥7) with complications. mtDNA4977 deletion, mtDNA copy number, adenine nucleotides, mitochondrial membrane potential and P‑selectin expression levels were analyzed in platelets. Although the frequency of mtDNA4977 deletion in platelets of the patient (96.9%) and control groups (95.6%) was extremely similar, the deletion level significantly increased in all the diabetic groups, compared with the healthy control group. However, the data from the present study revealed that an increased deletion frequency in platelets was not associated with disease severity, although there was clear interindividual variability. Furthermore, all other parameters were not significantly different among the groups, and there were no correlations between mtDNA4977 deletion frequency and all other studied parameters for any of the case groups. The results indicated that the mtDNA4977 deletion occurred in platelets, and increased deletion in patients with type 2 diabetes did not have a marked influence on mitochondrial and/or platelet dysfunction, when compared with the non‑diabetic subjects. Further research is required to elucidate the sources of inter‑individual variability observed in certain parameters.

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1	Smyth SS, McEver RP, Weyrich AS, Morrell CN, Hoffman MR, Arepally GM, French PA, Dauerman HL and Becker RC: 2009 Platelet Colloquium Participants: Platelet functions beyond hemostasis. J Thromb Haemost. 7:1759–1766. 2009. View Article : Google Scholar : PubMed/NCBI
2	Salem MA, Adly AA, Ismail EA, Darwish YW and Kamel HA: Platelets microparticles as a link between micro-and macro-angiopathy in young patients with type 1 diabetes. Platelets. 26:682–688. 2015. View Article : Google Scholar : PubMed/NCBI
3	Zhao LS, Lin YY, Liu Y, Xu CY, Liu Y, Bai WW, Tan XY, Li DZ and Xu JL: Doxazosin attenuates renal matrix remodeling mediated by anti-α₁-adrenergic receptor antibody in a rat model of diabetes mellitus. Exp Ther Med. 14:2543–2553. 2017. View Article : Google Scholar : PubMed/NCBI
4	Vinik AI, Erbas T, Park TS, Nolan R and Pittenger GL: Platelet dysfunction in type 2 diabetes. Diabetes Care. 24:1476–1485. 2001. View Article : Google Scholar : PubMed/NCBI
5	Sobel BE and Schneider DJ: Platelet function, coagulopathy, and impaired fibrinolysis in diabetes. Cardiol Clin. 22:511–526. 2004. View Article : Google Scholar : PubMed/NCBI
6	Michno A, Skibowska A, Raszeja-Specht A, Cwikowska J and Szutowicz A: The role of adenosine triphosphate citrate lyase in the metabolism of acetyl coenzyme a and function of blood platelets in diabetes mellitus. Metabolism. 53:66–72. 2004. View Article : Google Scholar : PubMed/NCBI
7	Skibowska A, Raszeja-Specht A and Szutowicz A: Platelet function and acetyl-coenzyme A metabolism in type 1 diabetes mellitus. Clin Chem Lab Med. 41:1136–1143. 2003. View Article : Google Scholar : PubMed/NCBI
8	Michno A, Bielarczyk H, Pawełczyk T, Jankowska-Kulawy A, Klimaszewska J and Szutowicz A: Alterations of adenine nucleotide metabolism and function of blood platelets in patients with diabetes. Diabetes. 56:462–467. 2007. View Article : Google Scholar : PubMed/NCBI
9	Daniel JL, Dangelmaier C, Jin J, Kim YB and Kunapuli SP: Role of intracellular signaling events in ADP-induced platelet aggregation. Thromb Haemost. 82:1322–1326. 1999. View Article : Google Scholar : PubMed/NCBI
10	Rolo AP and Palmeira CM: Diabetes and mitochondrial function: Role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol. 212:167–178. 2006. View Article : Google Scholar : PubMed/NCBI
11	Forbes JM, Coughlan MT and Cooper ME: Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes. 57:1446–1454. 2008. View Article : Google Scholar : PubMed/NCBI
12	Jay D, Hitomi H and Griendling KK: Oxidative stress and diabetic cardiovascular complications. Free Radic Biol Med. 40:183–192. 2006. View Article : Google Scholar : PubMed/NCBI
13	Yamagishi SI, Edelstein D, Du XL and Brownlee M: Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes. 50:1491–1494. 2001. View Article : Google Scholar : PubMed/NCBI
14	Porteous WK, James AM, Sheard PW, Porteous CM, Packer MA, Hyslop SJ, Melton JV, Pang CY, Wei YH and Murphy MP: Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion. Eur J Biochem. 257:192–201. 1998. View Article : Google Scholar : PubMed/NCBI
15	Wei YH: Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med. 217:53–63. 1998. View Article : Google Scholar : PubMed/NCBI
16	Krishnan KJ, Greaves LC, Reeve AK and Turnbull DM: Mitochondrial DNA mutations and aging. Ann N Y Acad Sci. 1100:227–240. 2007. View Article : Google Scholar : PubMed/NCBI
17	Drew B and Leeuwenburgh C: Ageing and subcellular distribution of mitochondria: Role of mitochondrial DNA deletions and energy production. Acta Physiol Scand. 182:333–341. 2004. View Article : Google Scholar : PubMed/NCBI
18	Botto N, Berti S, Manfredi S, Al-Jabri A, Federici C, Clerico A, Ciofini E, Biagini A and Andreassi MG: Detection of mtDNA with 4977 bp deletion in blood cells and atherosclerotic lesions of patients with coronary artery disease. Mutat Res. 570:81–88. 2005. View Article : Google Scholar : PubMed/NCBI
19	Lee HC, Pang CY, Hsu HS and Wei YH: Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim Biophys Acta. 1226:37–43. 1994. View Article : Google Scholar : PubMed/NCBI
20	Chuanzhong Y, Ming G, Fanglin Z, Haijiao C, Zhen L, Shiping C and YongKang Z: Real-time quantitative reverse transcription-PCR assay for renal cell carcinoma-associated antigen G250. Clin Chim Acta. 318:33–40. 2002. View Article : Google Scholar : PubMed/NCBI
21	Pushnova EA, Geier M and Zhu YS: An easy and accurate agarose gel assay for quantitation of bacterial plasmid copy numbers. Anal Biochem. 284:70–76. 2000. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delat C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Fiorentino TV, Prioletta A, Zuo P and Folli F: Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 19:5695–5703. 2013. View Article : Google Scholar : PubMed/NCBI
24	Liang P, Hughes V and Fukagawa NK: Increased prevalence of mitochondrial DNA deletions in skeletal muscle of older individuals with impaired glucose tolerance: Possible marker of glycemic stress. Diabetes. 46:920–923. 1997. View Article : Google Scholar : PubMed/NCBI
25	Kakimoto M, Inoguchi T, Sonta T, Yu HY, Imamura M, Etoh T, Hashimoto T and Nawata H: Accumulation of 8-hydroxy-2′-deoxyguanosine and mitochondrial DNA deletion in kidney of diabetic rats. Diabetes. 51:1588–1595. 2002. View Article : Google Scholar : PubMed/NCBI
26	Lu H, Koshkin V, Allister EM, Gyulkhandanyan AV and Wheeler MB: Molecular and metabolic evidence for mitochondrial defects associated with beta-cell dysfunction in a mouse model of type 2 diabetes. Diabetes. 59:448–459. 2010. View Article : Google Scholar : PubMed/NCBI
27	Yao YG, Ellison FM, McCoy JP, Chen J and Young NS: Age-dependent accumulation of mtDNA mutations in murine hematopoietic stem cells is modulated by the nuclear genetic background. Hum Mol Genet. 16:286–294. 2007. View Article : Google Scholar : PubMed/NCBI
28	Sandy MS, Langston JW, Smith MT and Di Monte DA: PCR analysis of platelet mtDNA: Lack of specific changes in Parkinson's disease. Mov Disord. 8:74–82. 1993. View Article : Google Scholar : PubMed/NCBI
29	Biagini G, Pallotti F, Carraro S, Sgarbi G, Pich MM, Lenaz G, Anzivino F, Gualandi G and Xin D: Mitochondrial DNA in platelets from aged subjects. Mech Ageing Dev. 101:269–275. 1998. View Article : Google Scholar : PubMed/NCBI
30	Tschoepe D, Roesen P, Esser J, Schwippert B, Nieuwenhuis HK, Kehrel B and Gries FA: Large platelets circulate in an activated state in diabetes mellitus. Semin Thromb Hemost. 17:433–438. 1991. View Article : Google Scholar : PubMed/NCBI
31	Watala C: Blood platelet reactivity and its pharmacological modulation in (people with) diabetes mellitus. Curr Pharm Des. 11:2331–2365. 2005. View Article : Google Scholar : PubMed/NCBI
32	Siewiera K, Kassassir H, Talar M, Wieteska L and Watala C: Higher mitochondrial potential and elevated mitochondrial respiration are associated with excessive activation of blood platelets in diabetic rats. Life Sci. 148:293–304. 2016. View Article : Google Scholar : PubMed/NCBI
33	Wu F, Liu Y, Luo L, Lu Y, Yew DT, Xu J and Guo K: Platelet mitochondrial dysfunction of DM rats and DM patients. Int J Clin Exp Med. 8:6937–6946. 2015.PubMed/NCBI
34	Avila C, Huang RJ, Stevens MV, Aponte AM, Tripodi D, Kim KY and Sack MN: Platelet mitochondrial dysfunction is evident in type 2 diabetes in association with modifications of mitochondrial anti-oxidant stress proteins. Exp Clin Endocrinol Diabetes. 120:248–251. 2012. View Article : Google Scholar : PubMed/NCBI
35	Rolf MG, Brearley CA and Mahaut-Smith MP: Platelet shape change evoked by selective activation of P2X1 purinoceptors with alpha, beta-methylene ATP. Thromb Haemost. 85:303–308. 2001. View Article : Google Scholar : PubMed/NCBI
36	Oury C, Toth-Zsamboki E, Thijs C, Tytgat J, Vermylen J and Hoylaerts MF: The ATP-gated P2X1 ion channel acts as a positive regulator of platelet responses to collagen. Thromb Haemost. 86:1264–1271. 2001. View Article : Google Scholar : PubMed/NCBI
37	Tang Y, Schon EA, Wilichowski E, Vazquez-Memije ME, Davidson E and King MP: Rearrangements of human mitochondrial DNA (mtDNA): New insights into the regulation of mtDNA copy number and gene expression. Mol Biol Cell. 11:1471–1485. 2000. View Article : Google Scholar : PubMed/NCBI
38	Fink BD, Herlein JA, O'Malley Y and Sivitz WI: Endothelial cell and platelet bioenergetics: Effect of glucose and nutrient composition. PLoS One. 7:e394302012. View Article : Google Scholar : PubMed/NCBI
39	Bray PF: Platelet hyperreactivity: Predictive and intrinsic properties. Hematol Oncol Clin North Am. 21:633–645. 2007. View Article : Google Scholar : PubMed/NCBI
40	O'donnell CJ, Larson MG, Feng D, Sutherland PA, Lindpaintner K, Myers RH, D'Agostino RA, Levy D and Tofler GH: Framingham Heart Study: Genetic and environmental contributions to platelet aggregation: The Framingham heart study. Circulation. 103:3051–3056. 2001. View Article : Google Scholar : PubMed/NCBI
41	Lemkes BA, Bähler L, Kamphuisen PW, Stroobants AK, Van Den Dool EJ, Hoekstra JB, Nieuwland R, Gerdes VE and Holleman F: The influence of aspirin dose and glycemic control on platelet inhibition in patients with type 2 diabetes mellitus. J Thromb Haemost. 10:639–646. 2012. View Article : Google Scholar : PubMed/NCBI
42	Al-Kafaji G and Golbahar J: High glucose-induced oxidative stress increases the copy number of mitochondrial DNA in human mesangial cells. Biomed Res Int. 2013:7549462013. View Article : Google Scholar : PubMed/NCBI
43	Pastukh VM, Gorodnya OM, Gillespie MN and Ruchko MV: Regulation of mitochondrial genome replication by hypoxia: The role of DNA oxidation in D-loop region. Free Radic Biol Med. 96:78–88. 2016. View Article : Google Scholar : PubMed/NCBI
44	Santos JM, Tewari S and Kowluru RA: A compensatory mechanism protects retinal mitochondria from initial insult in diabetic retinopathy. Free Radic Biol Med. 53:1729–1737. 2012. View Article : Google Scholar : PubMed/NCBI