Pgam5, also known as phosphoglycerate mutase family member 5, is a mitochondrial serine/threonine protein phosphatase. It plays a crucial role in mitochondrial dynamics, which includes processes like fusion, fission, biogenesis, and mitophagy [1,2,3]. PGAM5 is involved in multiple pathways related to programmed cell death, cellular senescence, and mitochondrial quality control, making it biologically significant in maintaining cellular homeostasis [1,2]. Genetic models, such as KO/CKO mouse models, are valuable tools for studying its functions.

Deletion of mitochondrial phosphatase PGAM5 in mice leads to accelerated retinal pigment epithelial (RPE) senescence both in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1. Its deletion leads to increased mitochondrial fusion and decreased turnover, causing elevated cellular ATP and ROS levels, enhanced mTOR and IRF/IFN-β signaling pathways, and ultimately cellular senescence [2].

In addition, genetic deletion of Pgam5 in various tumor-bearing mice ameliorates skeletal muscle atrophy by repressing excessive myoblast mitophagy and suppressing mitochondria meltdown and muscle wastage. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to maintain its continuous mitophagy, and S100A9-mediated activation of AGER/RAGE can promote the interaction between PGAM5 and BNIP3, leading to muscle wasting [4].

Conditional knockout of PGAM5 in macrophages greatly alleviates osteoarthritis symptoms and promotes anabolic metabolism of chondrocytes in vitro and in vivo. PGAM5 enhances M1 polarization via AKT-mTOR/p38/ERK pathways, while inhibits M2 polarization via STAT6-PPARγ pathway in murine bone marrow-derived macrophages. It also directly dephosphorylates DVL2, inhibiting β-catenin and repolarizing M2 macrophages into M1 macrophages [5].

In conclusion, Pgam5 plays essential roles in regulating mitochondrial dynamics, cellular senescence, and mitophagy. Studies using Pgam5 KO/CKO mouse models have revealed its significance in age-related diseases like RPE senescence, cancer-associated muscle wasting, and osteoarthritis. Understanding Pgam5's functions provides insights into the underlying mechanisms of these diseases and may offer potential therapeutic targets [2,4,5].