Cardiomyocyte βII spectrin plays a critical role in maintaining cardiac function by regulating mitochondrial respiratory function

Aims beta II spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of beta II spectrin in cardiac contractile function and pathological post-myocardial infarction remodelling remain unclear. Here, we investigated whether and how beta II spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischaemia/reperfusion (I/R) injury.Methods and results We observed that the levels of serum beta II spectrin breakdown products (beta II SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, beta II spectrin was degraded into beta II SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific beta II spectrin knockout mice, we found that deletion of beta II spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy, and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific beta II spectrin knockout mice had not developed, deletion of beta II spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of beta II spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that beta II spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, beta II spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75-kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability.Conclusion beta II spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in beta II spectrin exacerbate cardiac I/R injury. Graphical Abstract