PTPMT1 is a mitochondrial lipid and protein phosphatase essential for cardiolipin biosynthesis and mitochondrial function. Primary function: PTPMT1 dephosphorylates phosphatidylglycerophosphate (PGP) to phosphatidylglycerol (PG), a critical intermediate in cardiolipin synthesis 12. It also exhibits phosphatase activity toward mitochondrial proteins phosphorylated on serine/threonine residues, regulating ATP production 1. Mechanism: PTPMT1 contains a canonical protein tyrosine phosphatase domain with conserved EEYE loop critical for catalytic activity 2. It maintains mitochondrial membrane integrity and prevents intrinsic apoptosis by preserving cardiolipin homeostasis 13. Under hypoxia, HIF-2α induces PTPMT1 upregulation, which sustains glucose metabolism and cell proliferation 4. Disease relevance: Biallelic PTPMT1 variants cause autosomal recessive primary mitochondrial disease characterized by developmental delay, microcephaly, epilepsy, cerebellar atrophy, and sensorineural hearing loss 1. PTPMT1 is upregulated in small cell lung cancer 5, hepatocellular carcinoma 6, and pancreatic cancer 7, where it protects cells from ferroptosis. PTPMT1 variants have been identified in atypical diabetes cases 8, and mitochondrial dysfunction involving PTPMT1 contributes to Alzheimer's disease pathogenesis 9. Clinical significance: PTPMT1 inhibition represents a promising therapeutic strategy for cancer sensitization to ferroptosis-inducing agents, while PTPMT1 genetic screening may aid diagnosis of rare neurodevelopmental and metabolic disorders.