Syntabulin promotes heart failure by enhancing SR-mitochondria tethering and impairing mitofission.

Authors

Ying Li, Ziquan Sun, Haixia Duan, Mingyue Wu, Jing Yi, Gang Wang, Wenjuan Liu, Chenglin Zhang, Wanwen Cheng, Jicheng Li, Weixuan Chen, Kunfu Ouyang, Hui Tan, Yueheng Wu, Jie Liu

Published in

Cardiovascular research. Jun 29, 2026. Epub Jun 29, 2026.

Abstract

Mitochondrial dysfunction is a critical driver of heart failure (HF). Syntabulin (SYBU), known for its role as a motor linker at the outer mitochondrial membrane in neuronal system, has recently been suggested as a heart failure-associated gene. However, the role of SYBU in regulating cardiac function remains unclear.
Pressure overload-induced cardiac hypertrophy and HF was produced by transverse aortic constriction (TAC) in mice and phenylephrine (PE) stimulation in neonatal rat ventricular myocytes (NRVMs). SYBU expression was significantly increased in hypertrophic mouse hearts and patient hearts with dilated cardiomyopathy. The cardiac-specific upregulating SYBU expression, achieved via recombinant adeno-associated virus driven by cardiac troponin T promoter, led to increased cardiomyocyte death and worsened heart failure under hypertrophic conditions. In contrast, SYBU knockdown mitigated PE-induced cardiomyocyte injury. Structured illumination microscopy (SIM) and analysis of mitochondria-associated endoplasmic reticulum membrane (MAM) fractions revealed that SYBU localizes to ER-mitochondria contact sites. SYBU enhances sarcoplasmic reticulum (SR)-mitochondria tethering through interactions with RyR2 and SERCA2, leading to mitochondrial Ca2+ overload and impaired mitochondrial respiratory capacity. Furthermore, excessive mitochondrial Ca2+ triggered ER stress and PKA activation, inducing phosphorylation of Drp1 at Ser637, and ultimately disrupting mitochondrial fission and mitophagy.
Our findings established a critical role of SYBU in promoting HF by inducing cardiomyocyte injury via increasing SR-mitochondria tethering and impairing mitochondrial fission and mitophagy. Therefore, targeting SYBU and its downstream signaling pathways could be a promising therapeutic strategy to restrain HF in pressure overload - induced cardiac hypertrophy.

PMID:
42366787
Bibliographic data and abstract were imported from PubMed on 29 Jun 2026.

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