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The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria

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Autor(es):
Ronchi, Juliana Aparecida ; Francisco, Annelise ; Correa Passos, Luiz Augusto ; Figueira, Tiago Rezende ; Castilho, Roger Frigerio
Número total de Autores: 5
Tipo de documento: Artigo Científico
Fonte: Journal of Biological Chemistry; v. 291, n. 38, p. 20173-20187, SEP 16 2016.
Citações Web of Science: 24
Resumo

The forward reaction of nicotinamide nucleotide transhydrogenase (NNT) reduces NADP(+) at the expense of NADH oxidation and H+ movement down the electrochemical potential across the inner mitochondrial membrane, establishing an NADPH/NADP(+) ratio severalfold higher than the NADH/NAD(+) ratio in the matrix. In turn, NADPH drives processes, such as peroxide detoxification and reductive biosynthesis. In this study, we generated a congenic mouse model carrying a mutated Nnt(C57BL/6J) allele from the C57BL/6J substrain. Suspensions of isolated mitochondria from Nnt(+/+), Nnt(+/-), and Nnt(-/-) mouse liver were biochemically evaluated and challenged with exogenous peroxide under different respiratory states. The respiratory substrates were also varied, and the participation of concurrent NADPH sources (i.e. isocitrate dehydrogenase-2, malic enzymes, and glutamate dehydrogenase) was assessed. The principal findings include the following: Nnt(+/-) and Nnt(-/-) exhibit approximate to 50% and absent NNT activity, respectively, but the activities of concurrent NADPH sources are unchanged. The lack of NNT activity in Nnt(-/-) mice impairs peroxide metabolism in intact mitochondria. The contribution of NNT to peroxide metabolism is decreased during ADP phosphorylation compared with the non-phosphorylating state; however, it is accompanied by increased contributions of concurrent NADPH sources, especially glutamate dehydrogenase. NNT makes a major contribution to peroxide metabolism during the blockage of mitochondrial electron transport. Interestingly, peroxide metabolism in the Nnt(+/-) mitochondria matched that in the Nnt(+/+) mitochondria. Overall, this study demonstrates that the respiratory state and/or substrates that sustain energy metabolism markedly influence the relative contribution of NNT (i.e. varies between nearly 0 and 100%) to NADPH-dependent mitochondrial peroxide metabolism. (AU)

Processo FAPESP: 11/50400-0 - Metabolismo energético, estado redox e funcionalidade mitocondrial na morte celular e em desordens cardiometabólicas e neurodegenerativas
Beneficiário:Aníbal Eugênio Vercesi
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 15/22063-0 - Papel antioxidante da transidrogenase de nucleotídeos de nicotinamida (NNT) no sistema nervoso central - caracterização morfofuncional em camundongos controles e espontaneamente mutantes para o gene NNT
Beneficiário:Annelise Francisco
Linha de fomento: Bolsas no Brasil - Doutorado