Sirtuin 5 is required for mouse survival in response to cardiac pressure overload

J Biol Chem. 2017 Dec 1;292(48):19767-19781. doi: 10.1074/jbc.M117.809897. Epub 2017 Oct 2.


In mitochondria, the sirtuin SIRT5 is an NAD+-dependent protein deacylase that controls several metabolic pathways. Although a wide range of SIRT5 targets have been identified, the overall function of SIRT5 in organismal metabolic homeostasis remains unclear. Given that SIRT5 expression is highest in the heart and that sirtuins are commonly stress-response proteins, we used an established model of pressure overload-induced heart muscle hypertrophy caused by transverse aortic constriction (TAC) to determine SIRT5's role in cardiac stress responses. Remarkably, SIRT5KO mice had reduced survival upon TAC compared with wild-type mice but exhibited no mortality when undergoing a sham control operation. The increased mortality with TAC was associated with increased pathological hypertrophy and with key abnormalities in both cardiac performance and ventricular compliance. By combining high-resolution MS-based metabolomic and proteomic analyses of cardiac tissues from wild-type and SIRT5KO mice, we found several biochemical abnormalities exacerbated in the SIRT5KO mice, including apparent decreases in fatty acid oxidation and glucose oxidation as well as an overall decrease in mitochondrial NAD+/NADH. Together, these abnormalities suggest that SIRT5 deacylates protein substrates involved in cellular oxidative metabolism to maintain mitochondrial energy production. Overall, the functional and metabolic results presented here suggest an accelerated development of cardiac dysfunction in SIRT5KO mice in response to TAC, explaining increased mortality upon cardiac stress. Our findings reveal a key role for SIRT5 in maintaining cardiac oxidative metabolism under pressure overload to ensure survival.

Keywords: cardiac hypertrophy; cardiac metabolism; metabolomics; proteomics; sirtuin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / physiopathology*
  • Glucose / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria, Heart / metabolism
  • Oxidation-Reduction
  • Sirtuins / genetics
  • Sirtuins / physiology*
  • Survival Analysis
  • Systole


  • SIRT5 protein, mouse
  • Sirtuins
  • Glucose