Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload

The Journal of Biological Chemistry
Kathleen A HershbergerMatthew D Hirschey

Abstract

Mitochondrial Sirtuin 5 (SIRT5) is an NAD+-dependent demalonylase, desuccinylase, and deglutarylase that controls several metabolic pathways. A number of recent studies point to SIRT5 desuccinylase activity being important in maintaining cardiac function and metabolism under stress. Previously, we described a phenotype of increased mortality in whole-body SIRT5KO mice exposed to chronic pressure overload compared with their littermate WT controls. To determine whether the survival phenotype we reported was due to a cardiac-intrinsic or cardiac-extrinsic effect of SIRT5, we developed a tamoxifen-inducible, heart-specific SIRT5 knockout (SIRT5KO) mouse model. Using our new animal model, we discovered that postnatal cardiac ablation of Sirt5 resulted in persistent accumulation of protein succinylation up to 30 weeks after SIRT5 depletion. Succinyl proteomics revealed that succinylation increased on proteins of oxidative metabolism between 15 and 31 weeks after ablation. Heart-specific SIRT5KO mice were exposed to chronic pressure overload to induce cardiac hypertrophy. We found that, in contrast to whole-body SIRT5KO mice, there was no difference in survival between heart-specific SIRT5KO mice and their littermate controls. Overal...Continue Reading

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Citations

Jul 28, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Jaemin ByunJunichi Sadoshima
Dec 10, 2019·Horticulture Research·Xiaobing WangLikai Chen
Oct 30, 2020·Frontiers in Cell and Developmental Biology·Guo LiWei-Guo Zhu
Mar 9, 2021·Oxidative Medicine and Cellular Longevity·Jinlin LiuRui Guo
Apr 30, 2021·Journal of Molecular and Cellular Cardiology·Ashley FrancoisMatthew S Stratton
May 5, 2021·The Journal of Clinical Investigation·William GiblinDavid B Lombard
Aug 10, 2021·Frontiers in Cell and Developmental Biology·Boda ZhouTaotao Wei
Jul 29, 2021·American Journal of Physiology. Cell Physiology·Jessica N PeoplesJennifer Q Kwong

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