title: The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNA(Ile) A4263G mutation.
abstract: Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNA(Ile) A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca(2+) cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNA(Ile) A4263G mutation. The mitochondrial calcium ([Ca(2+)]m) in cells from hypertensive subjects with the tRNA(Ile) A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P<0.05). Meanwhile, cytosolic calcium ([Ca(2+)]c) in hypertensive with mutation cells was higher than another three groups. After exposure to caffeine, which could increase the [Ca(2+)]c by activating ryanodine receptor on endoplasmic reticulum, [Ca(2+)]c/[Ca(2+)]m increased higher than in hypertensive with mutation cells from another three groups. Moreover, MCU expression was decreased in hypertensive with mutation cells compared with in another three groups (P<0.05). [Ca(2+)]c increased and [Ca(2+)]m decreased after treatment with Ru360 (an inhibitor of MCU) or an siRNA against MCU. In this study we found decreased MCU expression in hypertensive with mutation cells contributed to dysregulated Ca(2+) uptake into the mitochondria, and cytoplasmic Ca(2+) overload. This abnormality might be involved in the underlying mechanisms of maternally inherited hypertension in subjects carrying the mitochondrial tRNA(Ile) A4263G mutation.
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Zhongqi
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Jinwen
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: ametuofo980869@163.com.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: liyangbsh@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006706:Homeostasis; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D024101:Mitochondrial Proteins; D009154:Mutation; D034741:RNA, Small Interfering / Q000235:genetics; D012355:RNA, Transfer, Ile / Q000235:genetics*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D012355:RNA, Transfer, Ile; C483046:SLC8B1 protein, human; D019831:Sodium-Calcium Exchanger; D050994:Voltage-Dependent Anion Channels; C034703:mitochondrial calcium uniporter; D002118:Calcium
keywords: Hypertension; Mitochondrial calcium cycle; Mitochondrial calcium uniporter; tRNA mutation