Int J Biol Sci 2024; 20(2):585-605. doi:10.7150/ijbs.83306 This issue Cite

Research Paper

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

Can Wei1, Meixin Shi1, Shiyun Dong1, Zhitao Li1, Bingbing Zhao1, Dan Liu2, Guopeng Li1, Jie Cen1, Ligen Yu1, Xiao Liang3, Lili Shi4,✉

1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, Heilongjiang, P.R. China.
2. Department of Cadre ward, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150081, Heilongjiang, P.R. China.
3. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150081, Heilongjiang, P.R. China.
4. Department of Cadre Ward, The First Affiliated Hospital of Harbin Medical University, Harbin, 150081, Heilongjiang, P.R. China.

Citation:
Wei C, Shi M, Dong S, Li Z, Zhao B, Liu D, Li G, Cen J, Yu L, Liang X, Shi L. SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy. Int J Biol Sci 2024; 20(2):585-605. doi:10.7150/ijbs.83306. https://www.ijbs.com/v20p0585.htm
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Abstract

Graphic 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.

Keywords: Diabetic cardiomyopathy, SIRT5, GSTP1, SPI1, Lysine malonylation


Citation styles

APA
Wei, C., Shi, M., Dong, S., Li, Z., Zhao, B., Liu, D., Li, G., Cen, J., Yu, L., Liang, X., Shi, L. (2024). SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy. International Journal of Biological Sciences, 20(2), 585-605. https://doi.org/10.7150/ijbs.83306.

ACS
Wei, C.; Shi, M.; Dong, S.; Li, Z.; Zhao, B.; Liu, D.; Li, G.; Cen, J.; Yu, L.; Liang, X.; Shi, L. SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy. Int. J. Biol. Sci. 2024, 20 (2), 585-605. DOI: 10.7150/ijbs.83306.

NLM
Wei C, Shi M, Dong S, Li Z, Zhao B, Liu D, Li G, Cen J, Yu L, Liang X, Shi L. SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy. Int J Biol Sci 2024; 20(2):585-605. doi:10.7150/ijbs.83306. https://www.ijbs.com/v20p0585.htm

CSE
Wei C, Shi M, Dong S, Li Z, Zhao B, Liu D, Li G, Cen J, Yu L, Liang X, Shi L. 2024. SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy. Int J Biol Sci. 20(2):585-605.

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