MPC1 is essential for PGC-1 alpha-induced mitochondrial respiration and biogenesis

Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates the transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and sternness. However, the mechanism by which MPC expression is regulated is largely unknown. In this study, we showed that MPC1 is down-regulated in human renal cell carcinoma (RCC) due to strong suppression of peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1 alpha (PGC-1 alpha). We also demonstrated that overexpression of PGC-1 alpha stimulates MPC1 transcription, while depletion of PGC-1 alpha by siRNA suppresses MPC expression. We found that PGC-1 alpha interacts with estrogen-related receptor-alpha (ERR-alpha) and recruits it to the ERR-alpha response element motif located in the proximal MPC1 promoter, resulting in efficient activation of MPC1 expression. Furthermore, the MPC inhibitor, UK5099, blocked PGC-1 alpha-induced pyruvate-dependent mitochondrial oxygen consumption. Taken together, our results suggest that MPC1 is a novel target gene of PGC-1 alpha. In addition, low expression of PGC-1 alpha in human RCC might contribute to the reduced expression of MPC, resulting in impaired mitochondrial respiratory capacity in RCC by limiting the transport of pyruvate into the mitochondrial matrix.