title: Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of type 1 diabetes.
abstract: Diabetic cardiomyopathy refers to the changes in contractility that occur to the diabetic heart that can arise in the absence of vascular disease. Mitochondrial bioenergetic deficits and increased free radical production are pathological hallmarks of diabetic cardiomyopathy, but the mechanisms and causal relationships between mitochondrial deficits and the progression of disease are not understood. We evaluated cardiac mitochondrial function in a rodent model of chronic Type 1 diabetes (OVE26 mice) before the onset of contractility deficits. We found that the most pronounced change in OVE26 heart mitochondria is severe metabolic inflexibility. This inflexibility is characterized by large deficits in mitochondrial respiration measured in the presence of non-fatty acid substrates. Metabolic inflexibility occurred concomitantly with decreased activities of PDH (pyruvate dehydrogenase) and complex II. Hyper-acetylation of protein lysine was also observed. Treatment of control heart mitochondria with acetic anhydride (Ac2O), an acetylating agent, preferentially inhibited respiration by non-fatty acid substrates and increased superoxide production. We have concluded that metabolic inflexibility, induced by discrete enzymatic and molecular changes, including hyper-acetylation of protein lysine residues, precedes mitochondrial defects in a chronic rodent model of Type 1 diabetes.
authors.affiliation: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, U.S.A.
authors.forename: Shraddha S
authors.initials: SS
authors.lastname: Vadvalkar
authors.forename: C Nathan
authors.initials: CN
authors.lastname: Baily
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuzaki
authors.forename: Melinda
authors.initials: M
authors.lastname: West
authors.forename: Yasvir A
authors.initials: YA
authors.lastname: Tesiram
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Humphries
mesh_terms: D000107:Acetylation; D000818:Animals; D002908:Chronic Disease; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology
chemical_list: D008239:Lysine