Serine/threonine-protein phosphatase PGAM5, mitochondrial

PGAM5 is a mitochondrial serine/threonine phosphatase that regulates multiple cellular processes through substrate dephosphorylation (UniProt: Q96HS1). It controls mitochondrial dynamics by dephosphorylating DNM1L/DRP1 to promote fission, protects MFN2 from degradation to support mitochondrial network formation, and modulates mitophagy via interaction with FUNDC1. PGAM5 also participates in anti-oxidative stress responses through interaction with KEAP1 and NRF2, and regulates necroptosis by recruiting the RIPK1-RIPK3-MLKL complex to mitochondria.

The protein is localized to mitochondria and functions in mitochondrial quality control and stress responses. No baseline disease associations are documented in UniProt.

PGAM5 is associated with Alzheimer's Disease and shows a downregulation pattern in AD brain tissue. In post-mortem AD brain compared to age-matched controls (Chaparral AD proteomics), PGAM5 demonstrates a mean log2 fold-change of −0.52, indicating reduced protein levels across the analyzed subcellular fraction. This downregulation may reflect compromised mitochondrial quality control and stress response capacity in the AD brain.