Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of Type 1 diabetes

• DOI: 10.1042/bj20121038
• Publication Date: 2012-10-04T08:28:35Z
• Authors: Shraddha S. Vadva...; C. Nathan Baily; Satoshi Matsuzaki; Melinda West; Yasvir A. Tesiram; Kenneth M. Humphries
• Keywords: Male; 0301 basic medicine; 0303 health sciences; 1303 Biochemistry; Diabetic Cardiomyopathies; Lysine; Diabetes; Free radicals; Acetylation; Mitochondria, Heart; 3. Good health; 1307 Cell Biology; Disease Models, Animal; Mice; 03 medical and health sciences; Diabetes Mellitus, Type 1; Cardiac mitochondria; Chronic Disease; 1312 Molecular Biology; Animals

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.