Diet-Sensitive Sources of Reactive Oxygen Species in Liver Mitochondria: Role of Very Long Chain Acyl-CoA Dehydrogenases

High fat diets and accompanying hepatic steatosis are highly prevalent conditions. Previous work has shown that steatosis is accompanied by enhanced generation of reactive oxygen species (ROS), which may mediate further liver damage. Here we investigated mechanisms leading to enhanced ROS generation following high fat diets (HFD). We found that mitochondria from HFD livers present no differences in maximal respiratory rates and coupling, but generate more ROS specifically when fatty acids are used as substrates. Indeed, many acyl-CoA dehydrogenase isoforms were found to be more highly expressed in HFD livers, although only the very long chain acyl-CoA dehydrogenase (VLCAD) was more functionally active. Studies conducted with permeabilized mitochondria and different chain length acyl-CoA derivatives suggest that VLCAD is also a source of ROS production in mitochondria of HFD animals. This production is stimulated by the lack of NAD+. Overall, our studies uncover VLCAD as a novel, diet-sensitive, source of mitochondrial ROS.

Supported by Fundação de Amparo à Pesquisa no Estado de São Paulo, Coordenadoria de Aperfeiçoamento do Pessoal do Ensino Superior, Conselho Nacional de Pesquisa e Desenvolvimento, Instituto Nacional de Ciência e Tecnologia de Processos Redox em Biomedicina and the Núcleo de Apoio à Pesquisa de Processos Redox em Biomedicina. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.