Mitochondrial pyruvate carrier inhibits tumor growth by Bmi1 ubiquitination in renal cell carcinoma progression.

Abstract

Mitochondrial pyruvate carrier (MPC), composed of MPC1 and MPC2, plays a pivotal role in regulating cancer metabolism. While previous studies have implicated MPC1 in tumor progression, the specific function of MPC2 in renal cell carcinoma (RCC) remains largely unclear. In this study, we found that reduced MPC2 expression was significantly associated with advanced TNM stage and poor patient prognosis. Functional assays demonstrated that MPC2 suppresses RCC cell proliferation both in vitro and in vivo. Additionally, concurrent low expression of MPC2 and MPC1 was correlated with significantly shorter overall survival, suggesting their combined prognostic value. Gene set enrichment analysis indicated that both MPC1 and MPC2 are negatively associated with the Bmi1 signaling pathway. Mechanistically, inhibition of the MPC complex-either genetically or pharmacologically-led to increased Bmi1 protein levels by reducing its ubiquitin-mediated degradation. These findings identify the MPC complex as a potential tumor suppressor and prognostic biomarker set in RCC, functioning in part through modulation of Bmi1 stability.