SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress

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.

AMPK, Mitochondrial Function, and Cardiovascular Disease

“…SIRT5, a member of the nicotinamide adenine dinucleotide-dependent sirtuin family of protein deacetylases, removes posttranslational modifications including malonylation, glutarylation, and succinylation on lysine residues [ 204 , 205 ]. SIRT5, primarily localizing at the mitochondrial matrix, plays a vital role in mitochondrial function via increased mitochondrial nicotinamide adenine dinucleotide and ATP synthase activity [ 138 ]. SIRT5 deficiency attenuated ATP production from mitochondrial ETC, increased the AMP-to-ATP ratio, and in turn activated AMPK in both cultured cells and hearts under the conditions of energy stress [ 138 ].…”

“…SIRT5, primarily localizing at the mitochondrial matrix, plays a vital role in mitochondrial function via increased mitochondrial nicotinamide adenine dinucleotide and ATP synthase activity [ 138 ]. SIRT5 deficiency attenuated ATP production from mitochondrial ETC, increased the AMP-to-ATP ratio, and in turn activated AMPK in both cultured cells and hearts under the conditions of energy stress [ 138 ]. Consistently, SIRT5 ablation attenuated cardiac hypertrophy and cardiac dysfunction in the TAC model, which is accompanied by the reduction of ATP, increase of AMP-to-ATP ratio, and enhancement of AMPK activity [ 138 ].…”

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…ContinuedHDACs Subcellular location Knockout and knockdown models ReferencesDecreases ATP production and activates AMP-activated protein kinase (AMPK) to attenuate cardiac hypertrophy of mice; heart-specific SIRT5 KO induces oxidative stress and cardiac hypertrophyHershberger et al, 2018;Zhang et al, 2019 …”

Sirtuins, Mitochondria and the Melatonergic Pathway in Alzheimer&rsquo;s Disease<strong> </strong>

“…Anti-ageing type effects driven by SIRT1 and nuclear factor erythroid 2-related factor (Nrf)2 in C. Elegans involve SIRT5 activation [40], paralleling the effects of SIRT1 in the deacetylation and activation of mitochondria-located SIRT3. The suppression of SIRT5 attenuates mitochondrial ATP production, as well as promoting AMP-activated protein kinase (AMPK) activation when under energy stress [41]. SIRT5 suppresses pancreatic β-cells proliferation and insulin secretion, with increased SIRT5 levels evident in type II diabetes patients [42], suggesting a role for SIRT5 in the association of type II diabetes with AD.…”