一个同时携带线粒体tRNAMet4435A>G和YARS2 c.5750A>C基因突变的原发性高血压家系的线粒体功能

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Abstract Objective: To explore the combined effects of m.4435A>G mutation and YARS2 c.5750A>C mutation on the mitochondrial function in patients with essential hypertension. Methods: Based on clinical manifestations, complete mitochondrial DNA sequences and YARS2 exon sequencing results, we searched and identified the proband and screened the extended family members with m.4435A>G gene mutation. Peripheral blood samples of the confirmed pedigree were collected and blood lymphocytes were translated into immortalized lymphoblastoid cell lines. After a period of culture, a series of experiments reflecting cell function were performed, including mitochondrial membrane potential (MMP) detection, intracellular reactive oxygen test (ROS) and Northern blot test. Results: Mitochondrial DNA sequence amplification was used to identify the proband and family members with m.4435A>G gene mutation. Further phylogenetic analysis revealed that the conservatism index of the 4435 loci reached 100%. With the successful establishment of immortalized cell lines, tRNA results showed that the steady-state level of the samples carrying m.4435A>G mutation decreased significantly, and tRNATyr steady-state level of the samples carrying YARS2 c.5750A>C mutation also significantly reduced. The extent to which tRNAMet decreased in the double mutant samples was greater than single mutation samples. Compared with the control group, the ROS levels containing m.4435A>G and YARS2 c.5750A>C gene mutant cell lines increased significantly, and the increased level of double mutants was higher than single mutations, with statistical difference (P<0.05). The decreased level of the mitochondrial membrane potential in cell lines of m.4435A>G and YARS2 c.5750A>C gene mutation was significantly higher than in the control group. Conclusion: The mutation of m.4435A>G and YARS2 c.5750A>C caused abnormal metabolism of tRNAMet and tRNATyr respectively, which finally led to cell dysfunction resulting from mitochondrial translation defects, increased ROS level and decreased MMP plus the increased mitochondrial mutation due to nuclear gene mutation. The results suggest that m.4435A>G and YARS2 c.5750A>C mutation plays an important role in the occurrence of essential hypertension in the family with essential hypertension.

Key words： essential hypertension mitochondrion tRNAMet tRNATyr mutation

Received: 05 December 2017

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	REN Xiaoyan
	CHEN Yaru
	SHI Wenwen
	ZHENG Binjiao
	XUE Ling
	GUAN MinXin

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https://xb.wmu.edu.cn/EN/ OR https://xb.wmu.edu.cn/EN/Y2018/V48/I7/479

[1] NIKITIN A G, LAVRIKOVA E Y, CHISTIAKOV D A. The heteroplasmic 15059G>A mutation in the mitochondrial cytochrome b gene and essential hypertension in type 2 diabe-tes[J]. Diabetes Metab Syndr, 2012, 6(3): 150-156.
[2] WATSON B JR, KHAN M A, DESMOND R A, et al. Mitochondrial DNA mutations in black Americans with hypertension-associated end-stage renal disease[J]. Am J Kidney Dis, 2001, 38(3): 529-536.
[3] NEDERLOF R, DENIS S, LAUZIER B, et al. Acute detachment of hexokinase II from mitochondria modestly increases oxygen consumption of the intact mouse heart[J]. Metabolism, 2017, 72: 66-74.
[4] SCHWARTZ F, DUKA A, SUN F, et al. Mitochondrial genome mutations in hypertensive individuals[J]. Am J Hypertens, 2004, 17(7): 629-635.
[5] GUAN M X, FISCHEL-GHODSIAN N, ATTARDI G. Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation[J]. Hum Mol Genet, 2001, 10(6): 573-580.
[6] MATTHIJS G, CLAES S, LONGO-MBENZA B, et al. Non-syndromic deafness associated with a mutation and a polymorphism in the mitochondrial 12S ribosomal RNA gene in a large Zairean pedigree[J]. Eur J Hum Genet, 1996, 4(1): 46-51.
[7] FUJII K, SUZUKI N, YAMAMOTO T, et al. Valproic acid inhibits proliferation of EB virus-infected natural killer cells [J]. Hematology, 2012, 17(3): 163-169.
[8] LIU B, WANG K, GAO H M, et al. Molecular consequences of activated microglia in the brain: overactivation induces apoptosis[J]. J Neurochem, 2001, 77(1): 182-189.
[9] TIAN Y Y, AN L J, JIANG L, et al. Catalpol protects dopaminergic neurons from LPS-induced neurotoxicity in mesencephalic neuron-glia cultures[J]. Life Sci, 2006, 80(3): 193-199.
[10] GRAS G, RICHARD Y, ROQUES P, et al. Complement and virus-specific antibody-dependent infection of normal B lymphocytes by human immunodeficiency virus type 1[J]. Blood, 1993, 81(7): 1808-1818.
[11] TAKAHASHI S. Astroglial protective mechanisms against ROS under brain ischemia[J]. Rinsho Shinkeigaku, 2011, 51 (11): 1032-1035.
[12] ATSUMI T, TONOSAKI K, FUJISAWA S. Induction of early apoptosis and ROS-generation activity in human gingival fibroblasts (HGF) and human submandibular gland carcinoma (HSG) cells treated with curcumin[J]. Arch Oral Biol, 2006, 51(10): 913-921.
[13] HAN Y H, MOON H J, YOU B R, et al. Pyrogallol-induced endothelial cell death is related to GSH depletion rather than ROS level changes[J]. Oncology Reports, 2010, 23(1): 287-292.
[14] STEUBE K G, GIGNAC S M, HU Z B, et al. In vitro culture studies of childhood myelodysplastic syndrome: establishment of the cell line MUTZ-1[J]. Leuk Lymphoma, 1997, 25(3-4): 345-363.
[15] OKUBO M, TSURUKUBO Y, HIGAKI T, et al. Clonal chromosomal aberrations accompanied by strong telomerase activity in immortalization of human B-lymphoblastoid cell lines transformed by Epstein-Barr virus[J]. Cancer Genet Cytogenet, 2001, 129(1): 30-34.
[16] GIEGE R, JUHLING F, PUTZ J, et al. Structure of transfer RNAs: similarity and variability[J]. Wiley Interdiscip Rev RNA, 2012, 3(1): 37-61.
[17] RILEY L G, COOPER S, HICKEY P, et al. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--
MLASA syndrome[J]. Am J Hum Genet, 2010, 87(1): 52-59.
[18] 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[J]. 生命科学, 2008(4): 496-505.
[19] JIANG P, JIN X, PENG Y, et al. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber’s hereditary optic neuropathy-associated mitochondrial DNA mutation[J]. Hum Mol Genet, 2016, 25(3): 584-596.
[20] DESAGHER S, MARTINOU J C. Mitochondria as the central control point of apoptosis[J]. Trends Cell Biol, 2000, 10 (9): 369-377.
[21] BEUREL E, JOPE R S. The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways[J]. Prog Neurobiol, 2006, 79(4): 173-189.