Phosphoglycerate 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.

中文翻译：

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非经典磷酸甘油酸脱氢酶活性通过线粒体翻译和呼吸代谢促进肝癌生长

磷酸甘油酸脱氢酶（PHGDH）是一种关键的丝氨酸生物合成酶，其异常表达可促进多种类型的肿瘤。近年来，PHGDH被发现具有丝氨酸生物合成之外的一些非经典功能，但其在肿瘤发生中的具体机制仍不清楚。在这里，我们发现 PHGDH 定位于线粒体内膜并促进肝癌细胞中线粒体 DNA (mtDNA) 编码蛋白的翻译。从机制上讲，我们证明线粒体PHGDH直接与腺嘌呤核苷酸转位酶2（ANT2）相互作用，然后招募线粒体延伸因子G2（mtEFG2）来促进线粒体核糖体回收效率，从而促进mtDNA编码的蛋白质表达和随后的线粒体呼吸。此外，我们发现用线粒体翻译抑制剂治疗或去除 mtEFG2 可以减少 PHGDH 介导的肿瘤生长。总的来说，我们的研究结果揭示了 PHGDH 在肿瘤发生中通过促进线粒体翻译和生物能发挥作用的先前未被认识到的功能。