SIRT3 improved peroxisomes-mitochondria interplay and prevented cardiac hypertrophy via preserving PEX5 expression.

Minghui Wang, Yanqing Ding, Yuehuai Hu, Zeyu Li, Wenwei Luo, Peiqing Liu, Zhuoming Li

Redox biology 2023 Jun

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The present study identified a novel mechanism underlying the protective effect of Sirtuin 3 (SIRT3) against pathological cardiac hypertrophy, beyond its well-accepted role as a deacetylase in mitochondria. SIRT3 modulates the peroxisomes-mitochondria interplay by preserving the expression of peroxisomal biogenesis factor 5 (PEX5), thereby improving mitochondrial function. Downregulation of PEX5 was observed in the hearts of Sirt3-/- mice and angiotensin II-induced cardiac hypertrophic mice, as well as in cardiomyocytes with SIRT3 silencing. PEX5 knockdown abolished the protective effect of SIRT3 against cardiomyocyte hypertrophy, whereas PEX5 overexpression alleviated the hypertrophic response induced by SIRT3 inhibition. PEX5 was involved in the regulation of SIRT3 in mitochondrial homeostasis, including mitochondrial membrane potential, mitochondrial dynamic balance, mitochondrial morphology and ultrastructure, as well as ATP production. In addition, SIRT3 alleviated peroxisomal abnormalities in hypertrophic cardiomyocytes via PEX5, as implied by improvement of peroxisomal biogenesis and ultrastructure, as well as increase of peroxisomal catalase and repression of oxidative stress. Finally, the role of PEX5 as a key regulator of the peroxisomes-mitochondria interplay was confirmed, since peroxisomal defects caused by PEX5 deficiency led to mitochondrial impairment. Taken together, these observations indicate that SIRT3 could maintain mitochondrial homeostasis by preserving the peroxisomes-mitochondria interplay via PEX5. Our findings provide a new understanding of the role of SIRT3 in mitochondrial regulation via interorganelle communication in cardiomyocytes. Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Minghui Wang, Yanqing Ding, Yuehuai Hu, Zeyu Li, Wenwei Luo, Peiqing Liu, Zhuoming Li. SIRT3 improved peroxisomes-mitochondria interplay and prevented cardiac hypertrophy via preserving PEX5 expression. Redox biology. 2023 Jun;62:102652