SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy

Abstract

Sirtuin 5 (SIRT5), localized in the mitochondria, has been identified as a protein desuccinylase and demalonylase in the mitochondria since the depletion of SIRT5 boosted the global succinylation and malonylation of mitochondrial proteins. We investigated the role of SIRT5 in diabetic cardiomyopathy (DCM) and identified the mechanism regarding lysine demalonylation in this process. Wild-type and SIRT5 knockout mice were induced with DCM, and primary cardiomyocytes and cardiac fibroblasts extracted from wild-type and SIRT5 knockout mice were subjected to high glucose (HG). SIRT5 deficiency exacerbated myocardial injury in DCM mice, aggravated HG-induced oxidative stress and mitochondrial dysfunction in cardiomyocytes, and intensified cardiomyocyte senescence, pyroptosis, and DNA damage. DCM-induced SIRT5 loss diminished glutathione S-transferase P (GSTP1) protein stability, represented by significantly increased lysine malonylation (Mal-Lys) modification of GSTP1. SIRT5 overexpression alleviated DCM-related myocardial injury, which was reversed by GSTP1 knockdown. Reduced SIRT5 transcription in DCM resulted from the downregulation of SPI1. SPI1 promoted the transcription of SIRT5, thereby ameliorating DCM-associated myocardial injury. However, SIRT5 deletion resulted in a significant reversal of the protective effect of SPI1. These observations suggest that SPI1 activates SIRT5 transcriptionally to mediate GSTP1 Mal-Lys modification and protein stability, thus ameliorating DCM-associated myocardial injury.

SIRT5-mediated desuccinylation prevents mitochondrial dysfunction in Alveolar epithelial cells senescence and Pulmonary fibrosis

“…However, AEC in the lung are active progenitors and secretory cells containing approximately 50% of lung mitochondrial mass (Hong et al 2023;Lee et al 2023), so it is reasonable to speculate that AEC senescence in IPF may be due to the occurrence of mitochondrial hyperKsucc. SIRT5, a mitochondrial sirtuin with very weak deacetylase activity, is a potent desuccinylase, the catalytic reaction involves the removal of a succinyl group from the lysine side chain of protein substrates (Wei et al 2024). SIRT5 as a global regulator of Ksucc in mitochondria has been reported that sirtuins depletion is related to the progression of pulmonary fibrosis, and increasing expression of sirtuins protein plays a protective role in pulmonary fibrosis (Shaikh et al 2019).…”