Syntaxin 17 Protects Against Heart Failure Through Recruitment of CDK1 to Promote DRP1-Dependent Mitophagy

Haixia Xu; Xiang Wang; Wenjun Yu; Shiqun Sun; Ne N Wu; Junbo Ge; Jun Ren; Yingmei Zhang

doi:10.1016/j.jacbts.2023.04.006

Syntaxin 17 Protects Against Heart Failure Through Recruitment of CDK1 to Promote DRP1-Dependent Mitophagy

JACC Basic Transl Sci. 2023 Jul 19;8(9):1215-1239. doi: 10.1016/j.jacbts.2023.04.006. eCollection 2023 Sep.

Authors

Haixia Xu^{1

2}, Xiang Wang¹, Wenjun Yu^{1

3}, Shiqun Sun¹, Ne N Wu¹, Junbo Ge¹, Jun Ren^{1

4}, Yingmei Zhang¹

Affiliations

¹ Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu, China.
³ Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁴ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

Abstract

Mitochondrial dysfunction is suggested to be a major contributor for the progression of heart failure (HF). Here we examined the role of syntaxin 17 (STX17) in the progression of HF. Cardiac-specific Stx17 knockout manifested cardiac dysfunction and mitochondrial damage, associated with reduced levels of p(S616)-dynamin-related protein 1 (DRP1) in mitochondria-associated endoplasmic reticulum membranes and dampened mitophagy. Cardiac STX17 overexpression promoted DRP1-dependent mitophagy and attenuated transverse aortic constriction-induced contractile and mitochondrial damage. Furthermore, STX17 recruited cyclin-dependent kinase-1 through its SNARE domain onto mitochondria-associated endoplasmic reticulum membranes, to phosphorylate DRP1 at Ser616 and promote DRP1-mediated mitophagy upon transverse aortic constriction stress. These findings indicate the potential therapeutic benefit of targeting STX17 in the mitigation of HF.

Keywords: CDK1; DRP1; MAMs; STX17; mitophagy; pressure overload–induced heart failure.