期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 91, 期 -, 页码 247-255出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.12.020
关键词
2-Oxoadipic acid dehydrogenase; DHTKDI; Reactive oxygen species; ROS; Skeletal muscle mitochondria; 2-Oxoacid dehydrogenase complexes
资金
- Brazilian Government through the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) e Conselhode Nacional de Desenvolvimento Cientifico e Tecnologico - programa Ciencias Sem Fronteiras (CNPq-CSF)
- Glenn Foundation
- Russian Science Foundation [N 14-15-00133]
- Russian Science Foundation [14-15-00133] Funding Source: Russian Science Foundation
In humans, mutations in dehydrogenase El and transketolase domain containing 1 (DHTKDI) are associated with neurological abnormalities and accumulation of 2-oxoadipate, 2-aminoadipate, and reactive oxygen species. The protein encoded by DHTKDI has sequence and structural similarities to 2-oxoglutarate dehydrogenase, and the 2-oxoglutarate dehydrogenase complex can produce superoxide/H2O2 at high rates. The DHTKDI enzyme is hypothesized to catalyze the oxidative decarboxylation of 2-oxoadipate, a shared intermediate of the degradative pathways for tryptophan, lysine and hydroxylysine. Here, we show that rat skeletal muscle mitochondria can produce superoxide/H2O2 at high rates when given 2-oxoadipate. We identify the putative mitochondrial 2-oxoadipate dehydrogenase complex as one of the sources and characterize the conditions that favor its superoxide/ H2O2 production. Rates increased at higher NAD(P)H/NAD(P)(+) ratios and were higher at each NAD(P)H/NAD(P)+ ratio when 2-oxoadipate was present, showing that superoxide/H2O2 was produced during the forward reaction from 2-oxoadipate, but not in the reverse reaction from NADH in the absence of 2-oxoadipate. The maximum capacity of the 2-oxoadipate dehydrogenase complex for production of superoxide/H2O2 is comparable to that of site IF of complex I, and seven, four and almost two-fold lower than the capacities of the 2-oxoglutarate, pyruvate and branched-chain 2-oxoacid dehydrogenase complexes, respectively. Regulation by ADP and ATP of H2O2 production driven by 2-oxoadipate was very different from that driven by 2-oxoglutarate, suggesting that site AF of the 2-oxoadipate dehydrogenase complex is a new source of superoxide/H2O2 associated with the NADH isopotential pool in mitochondria. (C) 2015 Elsevier Inc. All rights reserved.
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