2. Academic Validation
  3. Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2

Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2

  • Cell Signal. 2024 May 8:120:111219. doi: 10.1016/j.cellsig.2024.111219.
Yufei Zhou 1,  Le Kang 2,  Ran Xu 1,  Di Zhao 1,  Jienan Wang 1,  Jiaying Wu 3,  Hong Lin 1,  Zhiwen Ding 4,  Yunzeng Zou 5
Affiliations

Affiliations

  • 1 Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 3 Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 4 Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: zhiwen_d@fudan.edu.cn.
  • 5 Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: zou.yunzeng@zs-hospital.sh.cn.
PMID: 38723737 DOI: 10.1016/j.cellsig.2024.111219
Abstract

Cardiac remodeling is a critical process following myocardial infarction (MI), potentially leading to heart failure if untreated. The significance of mitochondrial homeostasis in MI remains insufficiently understood. Samm50 is an essential component of mitochondria. Our study aimed to investigate its role in hypoxia-induced cardiac injury and the underlying mechanisms. First, we observed that Samm50 was dynamically downregulated in mice with MI compared to the control mice. In vitro, Samm50 was also downregulated in oxygen-glucose-deprived neonatal rat cardiomyocytes and fibroblasts. Overexpression and knockdown of Samm50 mitigated and exacerbated cardiac Apoptosis and fibrosis, while also improving and worsening mitochondrial homeostasis, respectively. Protein interactions with Samm50 during the protective process were identified via immune-coprecipitation/mass spectroscopy. Mechanistically, serine hydroxymethyltransferase 2 (Shmt2) interacted with Samm50, acting as a crucial element in the protective process by hindering the transfer of Bax from the cytoplasm to the mitochondria and subsequent activation of Caspase-3. Inhibition of Shmt2 diminished the protective effect of Samm50 overexpression against cardiac injury. Finally, Samm50 overexpression in vivo mitigated cardiac remodeling and enhanced cardiac function in both acute and chronic MI. In conclusion, Samm50 overexpression mitigated hypoxia-induced cardiac remodeling by inhibiting Apoptosis and fibrosis, with Shmt2 acting as a key regulator in this protective process. The Samm50/Shmt2 axis represents a newly discovered mitochondria-related pathway for mitigating hypoxia-induced cardiac injury.

Keywords

Apoptosis; Fibrosis; Mitochondria; Myocardial infarction; Samm50; Shmt2.

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