Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation
Yuehuai Hu1, Yongjia Zheng2, Cui Liu1
1School of Pharmaceutical Sciences, National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
Abstract:
Lysine acetylation is a conserved post-translational modification involved in energy metabolism in mitochondria and heart function. This study investigates the role of mitochondria-localized lysine acetyltransferase MOF (males absent on the first) in heart failure (HF). We find that MOF is upregulated in mitochondria during HF, and overexpression of mitochondria-targeted MOF (mtMOF) in mouse models results in mitochondria dysfunction, cardiac remodeling, and HF. Furthermore, sirtuin 3 (SIRT3) knockout aggravates mtMOF-induced damages, underscoring the role of MOF-catalyzed hyperacetylation in HF. Quantitative lysine acetylome analysis identifies ATP5B as a substrate of MOF. We demonstrate that the acetylation of ATP5B at K201, co-regulated by MOF and SIRT3, impairs mitochondrial respiration and energy metabolism both in vitro and in vivo. These findings suggest that the role of MOF in HF could be attributed to its regulation of ATP5B acetylation. Overall, our results highlight the disruptive impact of mitochondrial MOF on cardiac function and emphasize the significance of enzyme-catalyzed acetylation in mitochondria.
Insights
Mitochondrial lysine acetyltransferase MOF (males absent on the first) upregulation exacerbates heart failure by impairing mitochondrial respiration and energy metabolism through ATP5B acetylation.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Mitochondrial Biology
Background:
- Lysine acetylation is a critical post-translational modification regulating mitochondrial function and heart health.
- Mitochondria-localized lysine acetyltransferase MOF (males absent on the first) role in heart failure (HF) remains largely unexplored.
Purpose of the Study:
- To investigate the role of mitochondria-localized MOF in the pathogenesis of heart failure.
- To elucidate the molecular mechanisms by which MOF affects cardiac function.
Main Methods:
- Utilized mouse models with overexpression of mitochondria-targeted MOF (mtMOF).
- Performed quantitative lysine acetylome analysis to identify MOF substrates.
- Investigated the impact of MOF and SIRT3 on ATP5B acetylation and mitochondrial function in vitro and in vivo.
Main Results:
- MOF is upregulated in mitochondria during HF and its overexpression induces mitochondrial dysfunction, cardiac remodeling, and HF.
- SIRT3 knockout exacerbates mtMOF-induced cardiac damage, indicating MOF-catalyzed hyperacetylation's detrimental role.
- Identified ATP5B as a MOF substrate, with acetylation at K201 impairing mitochondrial respiration and energy metabolism.
Conclusions:
- Mitochondrial MOF plays a significant role in the development and progression of heart failure.
- MOF-catalyzed acetylation of ATP5B disrupts mitochondrial respiration and energy metabolism, contributing to cardiac dysfunction.
- Targeting MOF or its substrates may offer novel therapeutic strategies for heart failure.
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