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 oxidoreductase) 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.
Department of Biochemistry and Pediatrics, University Medical Center Nijmegen, The Netherlands.
Henk-Jan
HJ
Visch
Guy A
GA
Rutter
Werner J H
WJ
Koopman
Jan B
JB
Koenderink
Sjoerd
S
Verkaart
Theun
T
de Groot
Aniko
A
Varadi
Kathryn J
KJ
Mitchell
Lambert P
LP
van den Heuvel
Jan A M
JA
Smeitink
Peter H G M
PH
Willems
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D001920:Bradykinin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002998:Clonazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency*; D005347:Fibroblasts / Q000378:metabolism; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007888:Leigh Disease / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013841:Thiazepines / Q000494:pharmacology; D013997:Time Factors
D005456:Fluorescent Dyes; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D015759:Ionomycin; D002998:Clonazepam; C079032:CGP 37157; D000255:Adenosine Triphosphate; D008156:Luciferases; D042967:Electron Transport Complex I; D010100:Oxygen; D001920:Bradykinin; D002118:Calcium