HDAC6 regulates mitochondrial oxidative phosphorylation by ATP synthase beta subunit acetylation in diabetic cardiomyopathy

Abstract

Diabetes‐induced cardiac mitochondrial dysfunction has been implicated as a trigger for pathogenesis in cardiac failure. Cardiac mitochondria consist of two distinct subpopulations, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). Our present work demonstrated that type 1 diabetic cardiac mitochondrial subpopulations have an abundance of acetylated proteins. We identified by mass spectrometry, 11 proteins that are acetylated in cardiac mitochondria of type 1 diabetic mice. ATP synthase beta subunit (ATP5B) was hyperacetylated in diabetic heart. For the first time we identified HDAC6 as a novel deactylator of mitochondrial proteins. HDAC6 contains an N‐terminal mitochondria targeting sequence which was confirmed by mass spectrometry. Cardiac mitochondrial basal levels of HDAC6 showed prominent differences between subpopulations. Further, diabetes‐induced cardiac mitochondrial HDAC6 expression is ablated in both subpopulations however IFM HDAC6 levels are more dramatically decreased. We observed a significantly increased level of acetyled ATP5B and decreased HDAC6 association in diabetic IFM. These findings identify acetylation as a novel regulatory mechanism for mitochondrial oxidative phosphorylation and that HDAC6 modulates mitochondrial intermediary metabolic molecules during the pathogenesis of diabetic cardiomyopathy. (Support: NIH DP2‐ DK083095)