线粒体DNA(mtDNA)突变是高血压发病的分子机制之一。已经报道的与原发性高血压相关的mtDNA突变包括: tRNAMet A4435G, tRNAMet/tRNAGln A4401G, tRNAIle A4263G, T4291C 和 A4295G突变。这些高血压相关的mtDNA突变改变了相应的线粒体tRNA的结构, 导致线粒体tRNA的代谢障碍。而线粒体tRNAs的代谢缺陷则影响蛋白质合成, 造成氧化磷酸化缺陷, 降低ATP的合成, 增加活性氧的产生。因此, 线粒体的功能缺陷可能在高血压的发生发展中起一定的作用。mtDNA突变发病的组织特异性则可能与线粒体tRNAs的代谢以及核修饰基因相关。目前发现的这些高血压相关的mtDNA突变则应该作为今后高血压诊断的遗传风险因子。高血压相关的线粒体功能缺陷的深入研究也将进一步诠释母系遗传高血压的分子致病机制, 为高血压的预防、 控制和治疗提供依据。文章对高血压相关的mtDNA突变进行了综述。
Mutations in mitochondrial DNA (mtDNA) are one of the molecular bases of hypertension. Among these, the tRNAMet A4435G, tRNAMet/tRNAGln A4401G, tRNAIle A4263G, T4291C and A4295G mutations have been reported to be associated with essential hypertension. These mutations alter the structure of the corresponding mitochondrial tRNAs and cause failures in tRNA metabolism. These shortages of these tRNAs lead to an impairment of mitochondrial protein synthesis and a failure in the oxidative phosphorylation function. These result in a deficit in ATP synthesis and an increase of generation of reactive oxygen species. As a result, these mitochondrial dysfunctions may contribute to the development of hypertension. Furthermore, the tissue specificity of these pathogenic mtDNA mutations might be associated with tRNA metabolism and nuclear modifier genes. These mtDNA mutations should be considered as inherited risk factors for future molecular diagnosis. Thus, these findings provide new insights into the molecular mechanism, management and treatment of maternally inherited hypertension. This review summarized the association between mtDNA mutations and hypertension.
[1] Gu DF, Reynolds K, Wu XG, Chen J, Duan XF, Muntner P, Huang GY, Reynolds RF, Su SY, Whelton PK, He J. Prevalence, awareness, treatment, and control of hyper-tension in China. Hypertension, 2002, 40(6): 920-927.
[2] 中国高血压防治指南修订委员会. 中国高血压防治指南(2005年修订版). 高血压杂志, 2005, 134(增刊): 2-41.
[3] Whitworth JA, World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH). J Hypertension, 2003, 21(11): 432.
[4] Brandão AP, Brandão AA, Araújo EM, Oliveira RC. Familial aggregation of arterial blood pressure and possible genetic influence. Hypertension, 1992, 19(Suppl.2): II214-II217.
[5] Watson B Jr, Khan MA, Desmond RA, Bergman S. Mitochondrial DNA mutations in black Americans with hypertension-associated end-stage renal disease. Am J Kidney Dis, 2001, 38(3): 529-536.
[6] Hirano M, Davidson M, DiMauro S. Mitochondria and the heart. Curr Opin Cardiol, 2001, 16(3): 201-210.
[7] Schwartz F, Duka A, Sun FZ, Cui J, Manolis A, Gavras H. Mitochondrial genome mutations in hypertensive individuals. Am J Hypertens, 2004, 17(7): 629-635.
[8] Wallace DC. Mitochondrial diseases in man and mouse. Science, 1999, 283(5407): 1482-1488.
[9] Schon EA, Bonilla E, DiMauro S. Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr, 1997, 29(2): 131-149.
[10] Anderson S, Bankier AT, Barrell BG, de Bruijn MHL, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJH, Staden R, Young IG. Sequence and organization of the human mitochondrial genome. Nature, 1981, 290(5806): 457-465.
[11] Attardi G, Schatz G. Biogenesis of mitochondria. Annu Rev Cell Biol, 1988, 4: 289-333.
[12] Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem, 1992, 61(1): 1175-1212.
[13] Giles RE, Blanc H, Cann HM, Wallace DC. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA, 1980, 77(11): 6715-6719.
[14] Jenuth JP, Peterson AC, Fu K, Shoubridge EA. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet, 1996, 14(2): 146-151.
[15] 严庆丰, 管敏鑫. 线粒体疾病与核基因－线粒体基因的表达调控. 生命科学, 2008, 20(4): 496-505.
[16] Wallace DC. Mitochondrial defects in cardiomyopathy and neuromuscular disease. Am Heart J, 2000, 139(2-3): S70-S85.
[17] Hutchin T, Cortopassi G. A mitochondrial DNA clone is associated with increased risk for Alzheimer disease. Proc Natl Acad Sci USA, 1995, 92(15): 6892-6895.
[18] Mayr-Wohlfarth U, Rödel G, Henneberg A. Mitochondrial tRNA(Gln) and tRNA(Thr) gene variants in Parkinson’s disease. Eur J Med Res, 1997, 2(3): 111-113.
[19] Perucca-Lostanlen D, Narbonne H, Hernandez JB, Staccini P, Saunieres A, Paquis-Flucklinger V, Vialettes B, Desnuelle C. Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome. Biochem Biophys Res Commun, 2000, 277(3): 771-775.
[20] Li XM, Li RH, Lin XH, Guan MX. Isolation and characterization of the putative nuclear modifier gene MTO1 involved in the pathogenesis of deafness-associated mitochondrial 12 S rRNA A1555G mutation. J Biol Chem, 2002, 277(30): 27256-27264.
[21] Brown MD, Starikovskaya E, Derbeneva O, Hosseini S, Allen JC, Mikhailovskaya IE, Sukernik RI, Wallace DC. The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. Hum Genet, 2002, 110(2): 130-138.
[22] Prezant TR, Agapian JV, Bohlman MC, Bu XD, Öztas S, Qiu WQ, Arnos KS, Cortopassi GA, Jaber L, Rotter JI, Shohat M, Fischel-Ghodsian N. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet, 1993, 4(3): 289-294.
