The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNAIle A4263G mutation |
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| Institution: | 1. Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA;2. School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA;3. School of Life Science, Tsinghua University, Beijing, 100084, PR China;1. Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;2. Department of Rheumatology, Charlotte Maxeke Johannesburg Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, South Africa;3. Rheumatology Division, Universitair Ziekenhuis and Vrije Universiteit Brussel, Belgium;1. Cardiothoracic Surgery of the First Affiliated Hospital, Hunan University of Traditional Chinese Medicine, Changsha, Hunan 41007, China;2. Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;3. Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;4. University of South China, College of Life Science, Department of Biochemistry and Molecular Biology, Hengyang, Hunan 421001, China;1. Ageing and Health, Ninewells Hospital, Dundee DD1 9SY, UK;2. Academic Geriatric Medicine, MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK |
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| Abstract: | Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNAIle A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca2+ cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNAIle A4263G mutation. The mitochondrial calcium (Ca2+]m) in cells from hypertensive subjects with the tRNAIle A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P < 0.05). Meanwhile, cytosolic calcium (Ca2+]c) in hypertensive with mutation cells was higher than another three groups. After exposure to caffeine, which could increase the Ca2+]c by activating ryanodine receptor on endoplasmic reticulum, Ca2+]c/Ca2+]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). Ca2+]c increased and Ca2+]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 Ca2+ uptake into the mitochondria, and cytoplasmic Ca2+ overload. This abnormality might be involved in the underlying mechanisms of maternally inherited hypertension in subjects carrying the mitochondrial tRNAIle A4263G mutation. |
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| Keywords: | Mitochondrial calcium uniporter Mitochondrial calcium cycle Hypertension tRNA mutation |
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