Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells

The mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) is a protein of interest in the transition from hepatic steatosis to hepatocellular carcinoma. Increased expression of PGAM5 in hepatocellular carcinoma correlates with reduced patient survival. Herein we demonstrate that loss of PGAM5 promotes mitochondrial oxidant injury and suppresses the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally, PGAM5 deletion reduces diacylglycerol concentrations by attenuating long-chain fatty acid uptake and suppressing its synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 in hepatocellular carcinoma.