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

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 HF-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 in mice and phenylephrine (PE) stimulation in neonatal rat ventricular myocytes. 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 HF under hypertrophic conditions. In contrast, SYBU knockdown mitigated PE-induced cardiomyocyte injury. Structured illumination microscopy and analysis of mitochondria-associated endoplasmic reticulum membrane fractions revealed that SYBU localizes to ER–mitochondria contact sites. SYBU enhances sarcoplasmic reticulum (SR)–mitochondria tethering through interactions with Ryanodine receptor 2 and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase, leading to mitochondrial Ca²⁺ overload and impaired mitochondrial respiratory capacity. Furthermore, excessive mitochondrial Ca²⁺ triggered ER stress and protein kinase A activation, inducing phosphorylation of dynamin-related protein 1 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 signalling pathways could be a promising therapeutic strategy to restrain HF in pressure overload–induced cardiac hypertrophy.