Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation

Lysine acetylation is a conserved post-translational modification involved in energy metabolism in mitochondria and heart function. This study investigates the role of mitochondria-localized lysine acetyltransferase MOF (males absent on the first) in heart failure (HF). We find that MOF is upregulated in mitochondria during HF, and overexpression of mitochondria-targeted MOF (mtMOF) in mouse models results in mitochondria dysfunction, cardiac remodeling, and HF. Furthermore, sirtuin 3 (SIRT3) knockout aggravates mtMOF-induced damages, underscoring the role of MOF-catalyzed hyperacetylation in HF. Quantitative lysine acetylome analysis identifies ATP5B as a substrate of MOF. We demonstrate that the acetylation of ATP5B at K201, co-regulated by MOF and SIRT3, impairs mitochondrial respiration and energy metabolism both in vitroand in vivo. These findings suggest that the role of MOF in HF could be attributed to its regulation of ATP5B acetylation. Overall, our results highlight the disruptive impact of mitochondrial MOF on cardiac function and emphasize the significance of enzyme-catalyzed acetylation in mitochondria.