Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis

It is unclear how the Warburg effect that exemplifies enhanced glycolysis in the cytosol is coordinated with suppressed mitochondrial pyruvate metabolism. We demonstrate here that hypoxia, EGFR activation, and expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1); this is mediated by ERK-dependent PGK1 S203 phosphorylation and subsequent PIN1-mediated cis-trans isomerization. Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. This reduces mitochondrial pyruvate utilization, suppresses reactive oxygen species production, increases lactate production, and promotes brain tumorigenesis. Furthermore, PGK1 S203 and PDHK1 T338 phosphorylation levels correlate with PDH S293 inactivating phosphorylation levels and poor prognosis in glioblastoma patients. This work highlights that PGK1 acts as a protein kinase in coordinating glycolysis and the tricarboxylic acid (TCA) cycle, which is instrumental in cancer metabolism and tumorigenesis. [Display omitted] •ERK and PIN1 regulate mitochondrial translocation of PGK1•PGK1, acting as a protein kinase, phosphorylates and activates PDHK1•PGK1 suppresses ROS production and coordinates glycolysis and the TCA cycle•Mitochondrial PGK1 promotes tumor cell proliferation and brain tumorigenesis PGK1 is a cytosolic glycolytic enzyme. Li et al. demonstrate that conditions such as hypoxia and oncogenic mutations that activate ERK signaling can induce mitochondrial translocation of PGK1. Mitochondrial PGK1, functioning as a protein kinase, phosphorylates and activates PDHK1 to suppress mitochondrial pyruvate metabolism and promotes the Warburg effect.