Affinage

PTPMT1

Phosphatidylglycerophosphatase and protein-tyrosine phosphatase 1 · UniProt Q8WUK0

Length
201 aa
Mass
22.8 kDa
Annotated
2026-06-10
28 papers in source corpus 17 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPMT1 is a mitochondria-resident dual-specificity phosphatase that catalyzes the committed step of cardiolipin biosynthesis by dephosphorylating phosphatidylglycerophosphate (PGP) to phosphatidylglycerol; loss of activity causes PGP accumulation and severe cardiolipin depletion, an effect rescued only by catalytically active enzyme (PMID:21641550). Crystal structures define a canonical dual-specificity PTP fold with a conserved EEYE catalytic loop and a substrate-bound active site that undergoes conformational change during catalysis (PMID:21730175), and both enzymatic activity and an intact mitochondrial localization signal are strictly required for biological function (PMID:21986498, PMID:23290137). Through cardiolipin production, PTPMT1 is essential for electron transport chain complex assembly, mitochondrial respiration, and normal mitochondrial morphology; its loss impairs oxygen consumption, drives compensatory glycolysis, and causes ROS accumulation and metabolic crisis (PMID:21641550, PMID:21986498, PMID:33503428). Beyond cardiolipin, PTPMT1 turns over phosphatidylinositol phosphate substrates that potentiate fatty-acid activation of UCP2 and influence mitochondrial fusion (PMID:21986498, PMID:23290137), and acts upstream of succinate dehydrogenase phosphorylation to govern glucose homeostasis (PMID:25660020). At the organismal level, PTPMT1 supports stem cell and hematopoietic differentiation, and tissue-specific deletion in heart and skeletal muscle blocks pyruvate utilization while forcing fatty acid oxidation, producing oxidative stress, muscle atrophy, heart failure, and sudden death (PMID:23290137, PMID:37672386). Biallelic loss-of-function variants in PTPMT1 cause an autosomal recessive primary mitochondrial disease with neurodevelopmental syndrome, with patient tissue showing impaired cardiolipin synthesis and mitochondrial dysfunction (PMID:39279645). The pseudophosphatase MK-STYX binds PTPMT1 and suppresses its activity, linking it to apoptotic control (PMID:24709986), and the selective inhibitor alexidine dihydrochloride engages PTPMT1 on-target (PMID:20167843).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    Establishing a chemical probe was the first step toward defining PTPMT1 function; identification of a selective small-molecule inhibitor enabled mechanism-based interrogation in primary tissue.

    Evidence In vitro phosphatase inhibition (IC50) plus PTPMT1 knockdown abolishing drug response in rat pancreatic islets

    PMID:20167843

    Open questions at the time
    • Did not define the physiological substrate
    • Mechanism linking PTPMT1 to insulin secretion left at protein-phosphorylation correlation
  2. 2011 High

    The central question of what PTPMT1 actually dephosphorylates was answered by identifying PGP as its substrate, defining PTPMT1 as the mammalian PGP phosphatase that commits lipid flux to cardiolipin.

    Evidence In vitro phosphatase assay with PGP, lipidomics of KO MEFs, and catalytic-dead rescue

    PMID:21641550

    Open questions at the time
    • Relative contribution of PIP versus PGP substrates not resolved
    • Whether PGP turnover alone accounts for all phenotypes unclear
  3. 2011 High

    Structural resolution of the phosphatase domain established the catalytic architecture, confirming a dual-specificity PTP fold and the functional EEYE loop.

    Evidence Apo and substrate-bound X-ray crystallography with EEYE loop mutagenesis and activity assays

    PMID:21730175

    Open questions at the time
    • Structure solved with PI5P, not the native PGP substrate
    • No structure of full-length membrane-embedded enzyme
  4. 2011 High

    Genetic ablation established the physiological necessity of PTPMT1, showing that loss impairs respiration and mitochondrial morphology and is embryonic-lethal, and that mitochondrial localization is required for differentiation.

    Evidence Whole-body and conditional KO mice and ES cells with respirometry, EM, lipidomics, and MLS-truncation rescue

    PMID:21641550 PMID:21986498

    Open questions at the time
    • Did not separate cardiolipin-dependent from PIP-dependent effects
    • Mechanism of differentiation block not fully resolved
  5. 2013 High

    PTPMT1 was connected to a second class of substrates and to apoptotic/metabolic control: its PIP products enhance UCP2 activation, and its loss triggers metabolic crisis and apoptosis in cancer cells.

    Evidence Hematopoietic-specific KO mice with catalytic and MLS rescue plus UCP2 assays; RNAi in cancer cells with cardiolipin, ATP, and apoptosis readouts

    PMID:23290137 PMID:23326511

    Open questions at the time
    • Direct enzymatic link between specific PIP species and UCP2 not structurally defined
    • Cancer-cell apoptosis mechanism partly correlative
  6. 2014 Medium

    The first negative regulator of PTPMT1 was identified, showing that pseudophosphatase MK-STYX binds and suppresses its catalytic activity to modulate apoptosis.

    Evidence MS interactome, Co-IP, activity suppression assays, and double-knockdown epistasis on cytochrome c release

    PMID:24709986

    Open questions at the time
    • Single lab without reciprocal in vivo validation
    • Structural basis of the inhibitory interaction unknown
  7. 2015 Medium

    A downstream effector branch was defined by genetic epistasis, placing PTPMT1 upstream of SDH phosphorylation in control of glucose homeostasis.

    Evidence Zebrafish chemical screen and ptpmt1 mutants with SDH phosphorylation/activity and glucose assays

    PMID:25660020

    Open questions at the time
    • Direct enzymatic mechanism linking PTPMT1 to SDH phosphorylation not shown
    • Single in vivo model
  8. 2018 Medium

    PTPMT1 expression was shown to be controlled at the splicing level, with SRSF1 directing isoform switching that affects AMPK signaling and radiation sensitivity.

    Evidence RNA-seq, RIP/CLIP, minigene reporters, SRSF1 knockdown in lung cancer cells and xenografts

    PMID:30429088

    Open questions at the time
    • Functional difference between short and full isoforms at the enzyme level not characterized
    • Single lab
  9. 2021 High

    The SRSF1–PTPMT1 splicing axis was mapped to a specific exon 3 binding motif and linked to AKT/C-MYC-driven oncogenesis, while a CRISPR screen established PTPMT1 as critical for hypoxic survival via cardiolipin-dependent ETC assembly.

    Evidence RIP-PCR/CLIP and minigene reporters in breast cancer; genome-wide CRISPR-Cas9 screen with KO, ETC assembly, ROS, and cardiolipin assays in HCC cells

    PMID:33503428 PMID:33992102

    Open questions at the time
    • Causal contribution of isoform switch to tumor phenotype only partial
    • ETC complex assembly defects shown biochemically but not at single-complex structural resolution
  10. 2023 High

    Tissue-specific genetics revealed metabolic selectivity, showing PTPMT1 is required for pyruvate utilization in heart and skeletal muscle but dispensable in liver and adipose, with loss forcing fatty acid oxidation and causing lethal organ failure.

    Evidence Tissue-specific KO mice with substrate oxidation, metabolomics, histology, and cardiac function assays; Co-IP linking PTPMT1 to SLC25A6/NDUFS2

    PMID:37034225 PMID:37672386

    Open questions at the time
    • Molecular basis of tissue selectivity unresolved
    • SLC25A6/NDUFS2 interactions are single Co-IP without reciprocal or mutagenesis validation
  11. 2025 High

    PTPMT1 was established as a human disease gene, with biallelic loss-of-function causing a recessive primary mitochondrial neurodevelopmental syndrome, and additional studies tied it to cardiac compaction, the integrated stress response, and ferroptosis susceptibility.

    Evidence Human genetics in 6 patients with patient-cell biochemistry and zebrafish KO; cardiac-specific KO with proliferation/ISR markers; HCC KO/overexpression with iron speciation and TCA metabolomics

    PMID:39279645 PMID:40189563 PMID:40700143

    Open questions at the time
    • Genotype–phenotype correlation across patients incomplete
    • Mechanism connecting cardiolipin loss to ISR activation and ferroptosis not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PTPMT1 partitions between its PGP/cardiolipin and phosphatidylinositol-phosphate substrate activities, and how this balance dictates tissue-specific metabolic, developmental, and cell-death outcomes, remains unresolved.
  • No quantitative substrate-flux model in vivo
  • Regulatory inputs controlling PTPMT1 activity beyond MK-STYX and splicing largely unknown
  • Structural basis of membrane substrate selection not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1643685 Disease 1
Partners
MK-STYXNDUFS2SLC25A6SRSF1UCP2

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 PTPMT1 specifically dephosphorylates phosphatidylglycerophosphate (PGP) in vitro, acting as the mammalian PGP phosphatase required for cardiolipin biosynthesis; loss of PTPMT1 leads to PGP accumulation and dramatic reduction of cardiolipin, rescued by catalytically active but not catalytically dead PTPMT1. In vitro phosphatase assay, lipid analysis of Ptpmt1-deficient mouse embryonic fibroblasts, catalytic-dead rescue experiment Cell Metabolism High 21641550
2011 Crystal structures of the PTPMT1 phosphatase domain reveal a canonical dual-specificity PTP fold; the substrate-bound structure (with phosphatidylinositol 5-phosphate) defines the active site architecture and shows significant conformational change during catalysis; a conserved EEYE loop was experimentally shown to be important for catalytic activity. X-ray crystallography (apo and substrate-bound), EEYE loop mutagenesis with activity assay Proceedings of the National Academy of Sciences of the United States of America High 21730175
2011 PTPMT1 localizes exclusively to mitochondria; its mitochondrial localization is required for function, as truncated PTPMT1 lacking the mitochondrial localization signal fails to rescue differentiation defects in Ptpmt1-knockout embryonic stem cells. Conditional knockout ES cells, rescue with wild-type vs. MLS-truncated PTPMT1 constructs, differentiation assays Molecular and Cellular Biology High 21986498 23290137
2011 Loss of Ptpmt1 in embryonic fibroblasts causes decreased mitochondrial respiration, abnormal mitochondrial morphology, PGP accumulation, and reduced cardiolipin; whole-body Ptpmt1 deletion leads to embryonic lethality. Whole-body and conditional Ptpmt1 knockout mice, oxygen consumption measurements, electron microscopy, lipidomics Cell Metabolism High 21641550
2011 Ptpmt1 depletion in embryonic stem cells blocks differentiation, increases cyclin-dependent kinase inhibitors, delays cell cycle, decreases oxygen consumption, and enhances glycolysis; accumulated phosphatidylinositol phosphates (PIPs) compromise mitochondrial fusion/dynamics. Conditional Ptpmt1 KO ES cells, cell cycle analysis, oxygen consumption and glycolysis assays, mitochondrial morphology imaging Molecular and Cellular Biology High 21986498
2013 PTPMT1 deficiency alters mitochondrial metabolism and its phosphatidylinositol phosphate substrates directly enhance fatty-acid-induced activation of mitochondrial uncoupling protein 2 (UCP2); catalytically deficient or MLS-lacking PTPMT1 fails to restore HSC differentiation, establishing catalytic activity and mitochondrial localization as essential. Inducible and hematopoietic-specific Ptpmt1 KO mice, rescue with WT vs. catalytic-dead vs. MLS-truncated PTPMT1, UCP2 activation assays Cell Stem Cell High 23290137
2015 PTPMT1 acts upstream of succinate dehydrogenase (SDH): pharmacological or genetic inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a mechanism by which PTPMT1 regulates glucose homeostasis in zebrafish; ptpmt1 mutation eliminates the glucose-lowering effect of alexidine, confirming SDH as the downstream effector. Chemical screen in zebrafish, ptpmt1 genetic mutants, SDH phosphorylation and activity assays, glucose measurements Cell Reports Medium 25660020
2010 Alexidine dihydrochloride is a selective inhibitor of PTPMT1 (IC50 ~1.08 μM in vitro); treatment of pancreatic islets increases insulin secretion, and knockdown of PTPMT1 renders islets insensitive to alexidine, confirming mechanism-based activity; PTPMT1 inhibition affects phosphorylation of mitochondrial proteins in beta cells. In vitro phosphatase inhibition assay, rat pancreatic islet insulin secretion assay, PTPMT1 knockdown in islets The Journal of Pharmacology and Experimental Therapeutics High 20167843
2014 The pseudophosphatase MK-STYX physically interacts with PTPMT1 and suppresses its catalytic activity; knockdown of PTPMT1 resensitizes MK-STYX-knockdown cells to chemotherapeutics and restores cytochrome c release, placing MK-STYX as a negative regulator of PTPMT1 in apoptosis control. Unbiased proteomics (MS interactome), co-immunoprecipitation confirmation in cells, PTPMT1 activity assays, cytochrome c release assays, double-knockdown epistasis PloS One Medium 24709986
2013 Downregulation of PTPMT1 in cancer cells decreases cardiolipin levels, selectively increases ATP levels in glycolytic media, and induces apoptosis; sublethal PTPMT1 knockdown synergizes with paclitaxel, suggesting PTPMT1 loss causes a metabolic crisis. RNAi knockdown in cancer cell lines, cardiolipin quantification, ATP measurement, apoptosis assays, drug synergy assay PloS One Medium 23326511
2023 PTPMT1 interacts with mitochondrial proteins SLC25A6 and NDUFS2 as identified by co-immunoprecipitation, suggesting PTPMT1 modulates mitochondrial function via the SLC25A6-NDUFS2 axis in pancreatic cancer cells. Co-immunoprecipitation, siRNA knockdown with viability and mitochondrial function assays American Journal of Cancer Research Low 37034225
2023 Cardiac-specific and skeletal-muscle-specific deletion of Ptpmt1 inhibits pyruvate (carbohydrate-derived substrate) utilization in mitochondria while enhancing fatty acid utilization, causing oxidative stress, mitochondrial destruction, lipid accumulation, muscle atrophy, heart failure, and sudden death; liver- or adipose-specific deletion has no such effect. Tissue-specific Ptpmt1 KO mice, substrate oxidation assays, metabolomics, histology, cardiac function measurements eLife High 37672386
2021 Knockout of PTPMT1 in hepatocellular carcinoma cells stops cardiolipin maturation and impairs assembly of electron transport chain (ETC) complexes, leading to electron leakage and ROS accumulation under hypoxia; PTPMT1 was identified as the top hit after HIF-1α/β in a genome-wide CRISPR-Cas9 knockout screen for hypoxic survival. Genome-wide CRISPR-Cas9 KO screen, PTPMT1 KO in HCC cells, ETC complex assembly assays, ROS measurement, cardiolipin quantification Cell Reports High 33503428
2025 Biallelic loss-of-function variants in PTPMT1 in humans cause an autosomal recessive primary mitochondrial disease with neurodevelopmental syndrome; patient-derived fibroblasts and muscle tissue show impaired cardiolipin biosynthesis, mitochondrial structural and functional defects; ptpmt1 knockout zebrafish show decreased total cardiolipin and OXPHOS deficiency, confirming the disease mechanism. Human genetics (biallelic variants in 6 patients), patient-derived fibroblast and muscle studies, cellular rescue experiments, ptpmt1 KO zebrafish with cardiolipin and OXPHOS measurements Brain High 39279645
2025 Pharmacological inhibition of PTPMT1 by alexidine dihydrochloride increases susceptibility of hepatocellular carcinoma to ferroptosis by promoting conversion of ferritin-bound Fe3+ to free Fe2+, expanding the labile iron pool, inducing mitochondrial swelling and donut mitochondria formation, and enhancing succinate-to-fumarate metabolism in the TCA cycle. PTPMT1 KO and overexpression in HCC cell lines (CRISPR/Cas9 and lentiviral), alexidine treatment in vitro and in vivo, iron speciation assays, mitochondrial morphology imaging, TCA metabolomics Cell Death & Disease Medium 40189563
2018 SRSF1 controls alternative splicing of PTPMT1; reduced SRSF1 favors production of short isoforms of PTPMT1 upon irradiation, which promotes AMPK phosphorylation and DNA double-strand breaks, sensitizing cancer cells to radiation. RNA-seq, RNA immunoprecipitation, minigene reporter assay, SRSF1 knockdown in lung cancer cell lines and xenografts EBioMedicine Medium 30429088
2021 SRSF1 directly binds a motif in PTPMT1 exon 3 to regulate splice switching; the resulting PTPMT1 isoform change partially mediates SRSF1 oncogenic effects via the AKT/C-MYC axis in breast cancer cells. RIP-PCR, CLIP, minigene reporter assay, functional rescue in breast cancer cell lines and xenografts Journal of Experimental & Clinical Cancer Research Medium 33992102
2025 Depleting PTPMT1 (or CRLS1) rescues apoptosis caused by BLTP1 deficiency, placing PTPMT1-dependent cardiolipin synthesis upstream of apoptotic cell death triggered by mitochondrial phospholipid overload; this establishes PTPMT1 in the genetic epistasis pathway of mitochondrial phospholipid efflux. Genetic epistasis by siRNA co-depletion of BLTP1 and PTPMT1, apoptosis assays bioRxiv (preprint)preprint Low bio_10.1101_2025.09.30.679455
2025 Cardiac-specific deletion of Ptpmt1 (αMHC-Cre) causes left ventricular non-compaction with reduced cardiomyocyte proliferation at E15.5 and increased phosphorylated eIF2α and ATF4, indicating a mitochondrial stress response links PTPMT1 to cardiac compaction and the integrated stress response pathway. Cardiac-specific KO mice, morphological/histological analysis, EdU proliferation assay, RNA-seq, western blot for p-eIF2α and ATF4 Journal of Developmental Biology Medium 40700143

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell stem cell 273 23290137
2011 Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis. Cell metabolism 176 21641550
2018 SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance. EBioMedicine 93 30429088
2021 Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1. Journal of experimental & clinical cancer research : CR 82 33992102
2010 Pharmacological targeting of the mitochondrial phosphatase PTPMT1. The Journal of pharmacology and experimental therapeutics 57 20167843
2015 PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation. Cell reports 54 25660020
2011 Structural and functional analysis of PTPMT1, a phosphatase required for cardiolipin synthesis. Proceedings of the National Academy of Sciences of the United States of America 51 21730175
2021 Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer. Cell reports 46 33503428
2011 A critical role of mitochondrial phosphatase Ptpmt1 in embryogenesis reveals a mitochondrial metabolic stress-induced differentiation checkpoint in embryonic stem cells. Molecular and cellular biology 39 21986498
2013 Downregulation of the mitochondrial phosphatase PTPMT1 is sufficient to promote cancer cell death. PloS one 30 23326511
2020 miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension. Molecular therapy. Nucleic acids 25 33335799
2014 The pseudophosphatase MK-STYX physically and genetically interacts with the mitochondrial phosphatase PTPMT1. PloS one 24 24709986
2011 Structure-based virtual screening approach to the discovery of novel PTPMT1 phosphatase inhibitors. Bioorganic & medicinal chemistry letters 20 22115589
2016 Ptpmt1 induced by HIF-2α regulates the proliferation and glucose metabolism in erythroleukemia cells. Biochemical and biophysical research communications 18 26898802
2023 PTPMT1 protects cardiomyocytes from necroptosis induced by γ-ray irradiation through alleviating mitochondria injury. American journal of physiology. Cell physiology 17 37154493
2025 Pharmacological targeting of the mitochondrial phosphatase PTPMT1 sensitizes hepatocellular carcinoma to ferroptosis. Cell death & disease 16 40189563
2025 Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome. Brain : a journal of neurology 12 39279645
2023 Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice. eLife 11 37672386
2011 PTPMT1: connecting cardiolipin biosynthesis to mitochondrial function. Cell metabolism 10 21641541
2020 A mitochondrial phosphatase PTPMT1 is essential for the early development of silkworm, Bombyx mori. Biochemical and biophysical research communications 8 32773109
2023 PTPMT1 regulates mitochondrial death through the SLC25A6-NDUFS2 axis in pancreatic cancer cells. American journal of cancer research 6 37034225
1994 Developmental expression of MOSP in cultured oligodendrocytes. Neurochemical research 5 7800116
2020 Drosophila PTPMT1 Has a Function in Tracheal Air Filling. iScience 4 32629421
2005 Firing up mitochondrial activities with PTPMT1. Molecular cell 4 16061174
2024 PTPMT1 inhibition induces apoptosis and growth arrest of human SCLC cells by disrupting mitochondrial metabolism. Translational cancer research 3 39816544
2023 Proteomic analysis by 4D label-free MS-PRM identified that Nptx1, Ptpmt1, Slc25a11, and Cpt1c are involved in diabetes-associated cognitive dysfunction. The International journal of neuroscience 2 38099467
2025 Deletion of Ptpmt1 by αMHC-Cre in Mice Results in Left Ventricular Non-Compaction. Journal of developmental biology 0 40700143
2022 The Mitochondrial Phosphatase PTPMT1 is Required for the Proper Growth Rate in the Red Flour Beetle, Tribolium castaneum. Zoological science 0 35699926

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