Abstract
Sirtuin 5 (SIRT5) is a member of the NAD+-dependent sirtuin family of protein deacylase that catalyzes removal of post-translational modifications, such as succinylation, malonylation, and glutarylation on lysine residues. In light of the SIRT5's roles in regulating mitochondrion function, we show here that SIRT5 deficiency leads to suppression of mitochondrial NADH oxidation and inhibition of ATP synthase activity. As a result, SIRT5 deficiency decreases mitochondrial ATP production, increases AMP/ATP ratio, and subsequently activates AMP-activated protein kinase (AMPK) in cultured cells and mouse hearts under energy stress conditions. Moreover, Sirt5 knockout attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy and cardiac dysfunction in mice, which is associated with decreased ATP level, increased AMP/ATP ratio and enhanced AMPK activation. Our study thus uncovers an important role of SIRT5 in regulating cellular energy metabolism and AMPK activation in response to energy stress.
Highlights
Large-scale proteomic surveys of cellular proteins have shown that lysine can be posttranslationally modified by diverse acylations, including acetylation [1], succinylation [2], malonylation [3], glutarylation [4], crotonylation [5], propionylation [6], and butyrylation [6]
We found that Sirtuin 5 (SIRT5) KO did not change cytosolic NADH level (S2 Fig and Fig 1B), but significantly increased the level of mitochondrial NADH by as much as 2.4-fold (P
Germline Sirt5 KO is well tolerated in mice [53, 55,56,57], and these animals exhibit no strong phenotypes with apparently normal size, body weight, food intake, mobility, and fertility under normal physiological conditions [53, 55,56,57]
Summary
Large-scale proteomic surveys of cellular proteins have shown that lysine can be posttranslationally modified by diverse acylations, including acetylation [1], succinylation [2], malonylation [3], glutarylation [4], crotonylation [5], propionylation [6], and butyrylation [6] The funder provided support in the form of salaries for authors (XXW and HW), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The other funders in our study had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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