title: Mitochondrial ATP-sensitive K(+) channels as redox signals to liver mitochondria in response to hypertriglyceridemia.
abstract: We have recently demonstrated that hypertriglyceridemic (HTG) mice present both elevated body metabolic rates and mild mitochondrial uncoupling in the liver owing to stimulated activity of the ATP-sensitive potassium channel (mitoK(ATP)). Because lipid excess normally leads to cell redox imbalance, we examined the hepatic oxidative status in this model. Cell redox imbalance was evidenced by increased total levels of carbonylated proteins, malondialdehydes, and GSSG/GSH ratios in HTG livers compared to wild type. In addition, the activities of the extramitochondrial enzymes NADPH oxidase and xanthine oxidase were elevated in HTG livers. In contrast, Mn-superoxide dismutase activity and content, a mitochondrial matrix marker, were significantly decreased in HTG livers. Isolated HTG liver mitochondria presented lower rates of H(2)O(2) production, which were reversed by mitoK(ATP) antagonists. In vivo antioxidant treatment with N-acetylcysteine decreased both mitoK(ATP) activity and metabolic rates in HTG mice. These data indicate that high levels of triglycerides increase reactive oxygen generation by extramitochondrial enzymes that promote mitoK(ATP) activation. The mild uncoupling mediated by mitoK(ATP) increases metabolic rates and protects mitochondria against oxidative damage. Therefore, a biological role for mitoK(ATP) as a redox sensor is shown here for the first time in an in vivo model of systemic and cellular lipid excess.
authors.affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13083-887 Campinas, SP, Brazil.
authors.forename: Luciane C
authors.initials: LC
authors.lastname: Alberici
authors.forename: Helena C F
authors.initials: HC
authors.lastname: Oliveira
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Paim
authors.forename: Camila C
authors.initials: CC
authors.lastname: Mantello
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Augusto
authors.forename: Karina G
authors.initials: KG
authors.lastname: Zecchin
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Gurgueira
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.forename: Anibal E
authors.initials: AE
authors.lastname: Vercesi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015228:Hypertriglyceridemia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D015221:Potassium Channels / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel