Inhibition of ACSF2 protects against renal ischemia/reperfusion injury via mediating mitophagy in proximal tubular cells

Acute kidney injury (AKI) is a prevalent clinical condition caused by sepsis and ischemia reperfusion (IR) injury. The principal driver of IR-induced AKI involves renal tubular structural changes triggered by the impairment of function in renal tubular cells. The target gene, Acyl-CoA Synthetase Family Member 2 (ACSF2), was retrieved from the GEO database based on high specific expression in renal tubular cells and location in mitochondria. Here, we substantiate that ACSF2 is specifically localized in the mitochondria of the renal tubular epithelium. Functionally silencing ACSF2 in HK2 cells enhanced hypoxia-reoxygenation (HR)-induced mitophagy, restored mitochondrial function and decreased the production of mitochondrial superoxide. Our study demonstrated that these effects were reversed by silencing Bcl-2 19-kDa interacting protein 3 (BNIP3), a receptor regulating mitophagy. In vivo, ACSF2 knockdown significantly enhanced IR-induced mitophagy and improved renal function in mice with IR injury. Conversely, BNIP3 knockdown inhibited mitophagy and exacerbated renal damage in ACSF2-knockdown mice with IR injury. In conclusion, our study demonstrated that inhibition of ACSF2 enhances mitophagy, restoring mitochondrial function and protects against IR-induced AKI, providing a new target and potential strategy for therapy.

Automated summary

Acute kidney injury (AKI) is a common clinical condition caused by sepsis and ischemia reperfusion (IR) injury. Impairment of function in renal tubular cells leads to renal tubular structural changes and ultimately AKI. In this study, we identified Acyl-CoA Synthetase Family Member 2 (ACSF2) as a target gene for its high specific expression in renal tubular cells and location in mitochondria. Silencing ACSF2 enhanced mitophagy, restored mitochondrial function, and protected against IR-induced AKI, suggesting ACSF2 as a potential therapeutic target.