USP13 inhibition exacerbates mitochondrial dysfunction and acute kidney injury by acting on MCL-1

Abstract

Acute kidney injury (AKI) is a globally recognized public health issue that lacks satisfactory therapeutic strategies. Deubiquitinase ubiquitin-specific protease 13 (USP13) regulates various pathophysiological processes via the deubiquitination of multiple substrates. However, its role in AKI remains unclear. To illustrate the role and underlying mechanism of USP13 in AKI, we subjected Usp13 knockdown mice, and mice treated with the USP13 inhibitor spautin-1, and mice with USP13 overexpression plasmids to cisplatin challenge. Renal tubular epithelial cell injury and mitochondrial disturbances were determined in vitro. Immunoprecipitation and deubiquitylation assays were performed to verify the interactions between USP13 and myeloid cell leukemia (MCL-1). We observed a significant decrease of USP13 expression in cisplatin-challenged AKI mice and renal tubular epithelial cells. Overexpression of USP13 alleviated kidney injury, whereas knockdown or inhibition of USP13 further exacerbated AKI. Mechanistically, USP13 downregulation resulted in increased degradation of MCL-1 which is a key regulator of cell survival and mitochondrial function, and the resultant MCL-1 reduction disrupted mitochondrial homeostasis and aggravated renal tubular epithelial cell injury and death, contributing to AKI progression. In conclusion, our findings demonstrated that inhibition of USP13 could exacerbate mitochondrial dysfunction and AKI through its effects on MCL-1, and USP13 may serve as a target for AKI prevention and treatment.