Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function

Significance Lysine succinylation is a recently discovered protein posttranslational modification and SIRT5 is an efficient desuccinylase. Although many mammalian proteins have recently been found to be regulated by lysine succinylation and SIRT5, the physiological significance of succinylation and SIRT5 remains unknown. Here we report that protein lysine succinylation predominantly accumulates in the heart when Sirt5 is deleted. Sirt5 -deficient mice exhibit defective fatty acid metabolism, decreased ATP production, and hypertrophic cardiomyopathy. Our data suggest that regulating heart metabolism and function is a major physiological role of lysine succinylation and SIRT5.