Unaltered Fatty Acid Uptake, Utilization, and Mitochondrial Respiration in Right Atrial Appendage of Type 2 Diabetic Human Heart

Abstract

Previous studies on diabetic human heart have shown decreased utilization of fatty acid (FA)/carbohydrate substrates. We hypothesized that increased mitochondrial dysfunction with concomitant decrease in fatty acid utilization would be found in diabetic hearts of patients from the Indian subcontinent that would explain their increased propensity of cardiovascular complications. We have compared mitochondrial respiration in atrial appendage tissue from nondiabetic and diabetic human subjects undergoing elective coronary artery bypass graft (CABG) surgery using high-resolution respirometry with FA and carbohydrate substrate combinations. In the presence of FA, diabetic mitochondria showed unimpaired complex I and electron transferring flavoprotein (ETF) mediated respiration while significantly lower oxygen consumption was noted when succinate was added, indicating the possible derangement of complex II respiration. Unlike other human studies, we report no significant reduction in FA- mediated mitochondrial respiration. However, the carbohydrate protocol indicated impairment of complex I mediated respiration. There was no significant change in the expression of OXPHOS proteins. Unchanged levels of FA uptake proteins like CD36 and FABP, FA oxidation enzyme, long chain acyl CoA deydrogenase (LCAD), regulators of FA metabolism like sirtuins and nuclear receptors, PPARα and transcription coactivators, PGC1α/β were observed in diabetic heart. The acetylation status of mitochondrial specific proteins involved in fatty acid oxidation (acetylated LCAD and PGC1α/β) also showed no significant changes. Diabetic patients showed equal expression of the antioxidant enzymes and other markers of oxidative stress. The unimpaired FA uptake, oxidation and mitochondrial respiration indicates absence of overt mitochondrial dysfunction in type 2 diabetic human heart. Disclosure N. Rj: None. R. Sr: None. V.V. Pillai: None. J. K.: None. S. Gopala: None.