Retinol saturase in the mitochondria antagonizes IDH2 and GLUD1 acetylation to mediate heart repair
Abstract
Facilitating endogenous cardiomyocyte proliferation has emerged as an important strategy for cardiac repair. Conserved retinol saturase (Retsat) functions in producing all-trans 13,14-dihydroretinol in the endoplasmic reticulum (ER). However, Retsat’s role and mechanism in heart regeneration remain unclear. Here, we uncover that Retsat is upregulated in cardiomyocytes during cardiac regeneration in mice. Cardiomyocyte-specific Retsat knockin promotes cardiac regeneration and improves cardiac function after injury. Conversely, cardiomyocyte-specific knockout of Retsat inhibits heart regeneration in neonatal mice. Surprisingly, Retsat drives cardiomyocyte proliferation independently of its classical retinol saturase activity in the ER. Retsat also localizes in cardiomyocyte mitochondria, and mitochondrial-specific overexpression of Retsat can stimulate cardiomyocyte proliferation and heart repair after injury. Mechanistically, Retsat in the mitochondria acts as an antagonist of Idh2 and Glud1 acetylation, reducing their acetylation levels and enhancing their activities. Furthermore, Retsat enters mitochondria by interacting with Tom70 and Tim23 proteins. These data suggest that targeting Retsat is a promising strategy for promoting cardiac regeneration after heart injury.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Wenya Ma
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Yanan Tian
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Jianglong Li
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Qimeng Ouyang
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Lei Xu
Bowei Zhang
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Hongyang Chen
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Hanjing Li
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Yuqing Lin
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Yu Hu
Zhongyu Ren
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Yifu Shen
Department of Laboratory Medicine at The Fourth Affiliated Hospital, Harbin Medical University
Xin Wang
Xinlu Gao
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University
Xiuxiu Wang
School of Life Sciences
Yining Liu
State Key Laboratory of Organ Regeneration and Reconstruction Beijing Institute for Stem Cell and Regenerative Medicine, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ye Tian
Yu Liu
Zhenwei Pan
Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Research, Ministry of Education, National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University
Benzhi Cai
Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University