In summary, we show in this study that SIRT5 deficiency suppresses mitochondrial NADH oxidation and ATP production at least in part through increasing lysine succinylation and enzymatic inhibition of ATP synthase, thereby contributing to decreased ATP production, higher AMP/ATP ratio, and enhanced AMPK activation in both cultured cells and an animal model for pressure overload-induced left ventricular hypertrophy. The gene discussed is SIRT5; the disease is left ventricular hypertrophy.