Inhibition of mitochondrial Na+-Ca2+ exchange restores agonist-induced ATP production and Ca2+ handling in human complex I deficiency

Human mitochondrial complex I (NADH:ubiquinone osidoreductase) of the oxidative phosphorylation system is a multiprotein assembly comprising both nuclear and mitochondrially encoded subunits. Deficiency of this complex is associated with numerous clinical syndromes ranging from highly progressive, often early lethal encephalopathies, of which Leigh disease is the most frequent, to neurodegenerative disorders in adult life, including Leber's hereditary optic neuropathy and Parkinson disease. We show here that the cytosolic Ca2+ signal in response to hormonal stimulation with bradykinin was impaired in skin fibroblasts from children between the ages of 0 and 5 years with an isolated complex I deficiency caused by mutations in nuclear encoded structural subunits of the complex. Inhibition of mitochondrial Na +-Ca2+ exchange by the benzothiazepine CGP37157 completely restored the aberrant cytosolic Ca2+ signal. This effect of the inhibitor was paralleled by complete restoration of the bradykinin-induced increases in mitochondrial Ca2+ concentration and ensuing ATP production. Thus, impaired mitochondrial Ca2+ accumulation during agonist stimulation is a major consequence of human complex I deficiency, a finding that may provide the basis for the development of new therapeutic approaches to this disorder.

Bibliographic Details

Main Authors:	Visch, Henk Jan, Rutter, Guy A., Koopman, Werner J.H., Koenderink, Jan B., Verkaart, Sjoerd, De Groot, Theun, Varadi, Aniko, Mitchell, Kathryn J., Van Den Heuvel, Lambert P., Smeitink, Jan A.H., Willems, Peter H.G.M.
Format:	Article/Letter to editor biblioteca
Language:	English
Subjects:	Life Science,
Online Access:	https://research.wur.nl/en/publications/inhibition-of-mitochondrial-nasupsup-casup2sup-exchange-restores-
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