Clinical and Genetic Analysis of Essential Hypertension with Gene M.15024G>A Mutation

Overview

Journal Zhejiang Da Xue Xue Bao Yi Xue Ban

Specialty General Medicine

Date 2023 Aug 29

PMID 37643984

Authors

Yunfan He

Wenxu Li

Zhen Liu

Juanjuan Zhang

Minxin Guan

Affiliations

Soon will be listed here.

Abstract

Objectives: To explore the role of mitochondrial 15024G>A mutation in the development of essential hypertension.

Methods: Mitochondrial genome sequences of hypertensive patients were obtained from previous studies. Clinical and genetic data of a hypertensive patient with mitochondrial 15024G>A mutation and its pedigree were analyzed. Lymphocytes derived from patient and family members were transformed into immortalized lymphoblastoid cell lines, and the levels of adenosine triphosphate (ATP), mitochondrial membrane potential and intracellular reactive oxygen species (ROS) were detected.

Results: The penetrance of this essential hypertension family was 42.9%, and the age of onset was 46-68 years old. Mitochondrial genome sequencing results showed that all maternal members carried a highly conserved mitochondrial 15024G>A mutation. This mutation could affect the free energy of mitochondrial CYB for secondary and tertiary structure and protein folding, thereby changing its structural stability and the structure of the electron transfer function area around the mutation site. Compared with the control, the cell line carrying the mitochondrial 15024G>A mutation showed significantly decreased levels of mitochondrial CYB, ATP and mitochondrial membrane potential, and increased levels of ROS (<0.01).

Conclusions: Mitochondrial 15024G>A mutation may affect the structure of respiratory chain subunits and mitochondrial function, leading to cell dysfunction, which suggests that the mutation may play a synergistic role in essential hypertension.

References

Ait-Aissa K, Blaszak S, Beutner G, Tsaih S, Morgan G, Santos J . Mitochondrial Oxidative Phosphorylation defect in the Heart of Subjects with Coronary Artery Disease. Sci Rep. 2019; 9(1):7623. PMC: 6527853. DOI: 10.1038/s41598-019-43761-y. View

Merante F, Myint T, Tein I, Benson L, Robinson B . An additional mitochondrial tRNA(Ile) point mutation (A-to-G at nucleotide 4295) causing hypertrophic cardiomyopathy. Hum Mutat. 1996; 8(3):216-22. DOI: 10.1002/(SICI)1098-1004(1996)8:3<216::AID-HUMU4>3.0.CO;2-7. View

Bandelt H, Kloss-Brandstatter A, Richards M, Yao Y, Logan I . The case for the continuing use of the revised Cambridge Reference Sequence (rCRS) and the standardization of notation in human mitochondrial DNA studies. J Hum Genet. 2013; 59(2):66-77. DOI: 10.1038/jhg.2013.120. View

Gong S, Peng Y, Jiang P, Wang M, Fan M, Wang X . A deafness-associated tRNAHis mutation alters the mitochondrial function, ROS production and membrane potential. Nucleic Acids Res. 2014; 42(12):8039-48. PMC: 4081083. DOI: 10.1093/nar/gku466. View

Mahfouz R, Sharma R, Lackner J, Aziz N, Agarwal A . Evaluation of chemiluminescence and flow cytometry as tools in assessing production of hydrogen peroxide and superoxide anion in human spermatozoa. Fertil Steril. 2008; 92(2):819-27. DOI: 10.1016/j.fertnstert.2008.05.087. View

Kirkman D, Robinson A, Rossman M, Seals D, Edwards D . Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases. Am J Physiol Heart Circ Physiol. 2021; 320(5):H2080-H2100. PMC: 8163660. DOI: 10.1152/ajpheart.00917.2020. View

Chiong M, Cartes-Saavedra B, Norambuena-Soto I, Mondaca-Ruff D, Morales P, Garcia-Miguel M . Mitochondrial metabolism and the control of vascular smooth muscle cell proliferation. Front Cell Dev Biol. 2015; 2:72. PMC: 4266092. DOI: 10.3389/fcell.2014.00072. View

Li Z, Liu Y, Yang L, Wang S, Guan M . Maternally inherited hypertension is associated with the mitochondrial tRNA(Ile) A4295G mutation in a Chinese family. Biochem Biophys Res Commun. 2008; 367(4):906-11. DOI: 10.1016/j.bbrc.2007.12.150. View

Zhao X, Cui L, Xiao Y, Mao Q, Aishanjiang M, Kong W . Hypertension-associated mitochondrial DNA 4401A>G mutation caused the aberrant processing of tRNAMet, all 8 tRNAs and ND6 mRNA in the light-strand transcript. Nucleic Acids Res. 2019; 47(19):10340-10356. PMC: 6821173. DOI: 10.1093/nar/gkz742. View

10.

Song Z, Laleve A, Vallieres C, McGeehan J, Lloyd R, Meunier B . Human Mitochondrial Cytochrome b Variants Studied in Yeast: Not All Are Silent Polymorphisms. Hum Mutat. 2016; 37(9):933-41. PMC: 5094555. DOI: 10.1002/humu.23024. View

11.

Sun J, Zhao X, Qiao L, Mei S, Nie Z, Zhang Q . Cellular models for mitochondrial DNA-based diseases: lymphoblastoid cell lines and transmitochondrial cybrids. Yi Chuan. 2016; 38(7):666-673. DOI: 10.16288/j.yczz.16-085. View

12.

Eirin A, Lerman A, Lerman L . Mitochondrial injury and dysfunction in hypertension-induced cardiac damage. Eur Heart J. 2014; 35(46):3258-66. PMC: 4258226. DOI: 10.1093/eurheartj/ehu436. View

13.

Qiu Q, Li R, Jiang P, Xue L, Lu Y, Song Y . Mitochondrial tRNA mutations are associated with maternally inherited hypertension in two Han Chinese pedigrees. Hum Mutat. 2012; 33(8):1285-93. DOI: 10.1002/humu.22109. View

14.

Kearney P, Whelton M, Reynolds K, Muntner P, Whelton P, He J . Global burden of hypertension: analysis of worldwide data. Lancet. 2005; 365(9455):217-23. DOI: 10.1016/S0140-6736(05)17741-1. View

15.

Wallace D . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39:359-407. PMC: 2821041. DOI: 10.1146/annurev.genet.39.110304.095751. View

16.

Hajjar I, Kotchen T . Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA. 2003; 290(2):199-206. DOI: 10.1001/jama.290.2.199. View

17.

Wang S, Li R, Fettermann A, Li Z, Qian Y, Liu Y . Maternally inherited essential hypertension is associated with the novel 4263A>G mutation in the mitochondrial tRNAIle gene in a large Han Chinese family. Circ Res. 2011; 108(7):862-70. DOI: 10.1161/CIRCRESAHA.110.231811. View

18.

Chobanian A, Bakris G, Black H, Cushman W, Green L, Izzo Jr J . The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289(19):2560-72. DOI: 10.1001/jama.289.19.2560. View

19.

Gratl A, Wipper S, Frese J, Raude B, Greiner A, Pesta D . The Role of Mitochondrial Function in Peripheral Arterial Disease: Insights from Translational Studies. Int J Mol Sci. 2021; 22(16). PMC: 8395190. DOI: 10.3390/ijms22168478. View

20.

Zhou M, Wang M, Xue L, Lin Z, He Q, Shi W . A hypertension-associated mitochondrial DNA mutation alters the tertiary interaction and function of tRNA. J Biol Chem. 2017; 292(34):13934-13946. PMC: 5572913. DOI: 10.1074/jbc.M117.787028. View