Methylcrotonyl-CoA carboxylase 2 supports leucine catabolism to promote mitochondrial biogenesis and alleviate cisplatin-induced acute kidney injury.

Background: Cisplatin is widely used in clinical practice, but its nephrotoxicity severely limits its use. Previous studies have shown that cisplatin-induced acute kidney injury (AKI) is closely related to mitochondrial damage and that alleviating mitochondrial dysfunction can alleviate cisplatin-induced AKI. Methylcrotonyl‑CoA carboxylase 2 (MCCC2) is mainly located in mitochondria, where it catalyzes the catabolism of leucine and maintains mitochondrial function; however, the role of MCCC2 in cisplatin-induced renal injury has not yet been studied.

Methods: In vitro, the expression of MCCC2 was manipulated by transfecting HK-2 cells with lentiviruses, and changes in the acetoacetate content, cell viability, apoptosis, oxidative stress, mitochondrial function, and mitochondrial biogenesis were evaluated. In vivo, MCCC2 overexpression was manipulated by adeno-associated viruses, and serum and kidneys were collected for subsequent experiments to detect changes in renal function, tissue damage, apoptosis, oxidative stress, mitochondrial damage, and mitochondrial biogenesis.

Results: We found that MCCC2 was downregulated in cisplatin-induced AKI models. In vitro, leucine catabolism was inhibited by cisplatin, while overexpression of MCCC2 supported leucine catabolism, upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression, promoted mitochondrial biogenesis, improved mitochondrial function, and alleviated cisplatin-induced apoptosis and oxidative stress in HK-2 cells. In contrast, the knockdown of MCCC2 exacerbated these effects, while leucine deprivation reversed the effects of MCCC2 overexpression on mitochondrial function and biogenesis. In vivo, the overexpression of MCCC2 promoted mitochondrial biogenesis, maintained the integrity of the mitochondrial structure and function, and alleviated cisplatin-induced AKI.

Conclusion: MCCC2 supported leucine catabolism and promoted mitochondrial biogenesis, providing a new therapeutic strategy for cisplatin-induced AKI.