Non‐canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism

• DOI: 10.15252/embj.2022111550
• Publication Date: 2022-10-31T13:00:48Z
• Authors: Ying Shu; Yijie Hao; Junru Feng; Haiying Liu; Shi‐ting Li; Jiaqian Feng; Zetan Jiang; Ling Ye; Yingli Zhou; Yuchen Sun; Zilong Zhou; Haoran Wei; Ping Gao; Huafeng Zhang; Linchong Sun
• Keywords: 0301 basic medicine; 03 medical and health sciences; Carcinogenesis; Cell Line, Tumor; Liver Neoplasms; Serine; Humans; DNA, Mitochondrial; Phosphoglycerate Dehydrogenase; 3. Good health

AbstractPhosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non‐canonical functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)‐encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA‐encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH‐mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.