The Ablation of Mitochondrial Protein Phosphatase Pgam5 Confers Resistance Against Metabolic Stress

• The ablation of Pgam5, a mitochondria-resident protein phosphatase, protected mice from some metabolic stresses.
• Pgam5-deficient mice were resistant to a cold plus fasting stress and a high fat diet-induced obesity.
• Our study revealed that PGAM5 acts as a metabolic regulator in vivo.Here, we revealed that the ablation of Pgam5, a mitochondria-resident protein phosphatase, protects mice from some metabolic stresses. When fasted mice were exposed to cold condition, Pgam5 deficiency promoted the lipid metabolism and the expression of metabolic hormone FGF21 in brown adipose tissue, a center of heat production, suggesting that these metabolic changes might ultimately contribute to their resistance. In addition, we found that Pgam5-deficient mice were dramatically resistant to high-fat diet-induced obesity. Our study not only provides the evidence that PGAM5 acts as a metabolic regulator in vivo but also raises the potential therapeutic target for metabolic diseases.

Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial protein phosphatase that has been reported to be involved in various stress responses from mitochondrial quality control to cell death. However, its roles in vivo are largely unknown. Here, we show that Pgam5-deficient mice are resistant to several metabolic insults. Under cold stress combined with fasting, Pgam5-deficient mice better maintained body temperature than wild-type mice and showed an extended survival rate. Serum triglycerides and lipid content in brown adipose tissue (BAT), a center of adaptive thermogenesis, were severely reduced in Pgam5-deficient mice. Moreover, although Pgam5 deficiency failed to maintain proper mitochondrial integrity in BAT, it reciprocally resulted in the dramatic induction of fibroblast growth factor 21 (FGF21) that activates various functions of BAT including thermogenesis. Thus, the enhancement of lipid metabolism and FGF21 may contribute to the cold resistance of Pgam5-deficient mice under fasting condition. Finally, we also found that Pgam5-deficient mice are resistant to high-fat-diet-induced obesity. Our study uncovered that PGAM5 is involved in the whole-body metabolism in response to stresses that impose metabolic challenges on mitochondria.