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Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis.

PTPMT1 was the first protein tyrosine phosphatase found localized to the mitochondria, but its biological function was unknown. Herein, we demonstrate that whole body deletion of Ptpmt1 in mice leads to embryonic lethality, suggesting an indispensable role for PTPMT1 during development. Ptpmt1 deficiency in mouse embryonic fibroblasts compromises mitochondrial respiration and results in abnormal mitochondrial morphology. Lipid analysis of Ptpmt1-deficient fibroblasts reveals an accumulation of phosphatidylglycerophosphate (PGP) along with a concomitant decrease in phosphatidylglycerol. PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis.

Pubmed ID: 21641550

Authors

  • Zhang J
  • Guan Z
  • Murphy AN
  • Wiley SE
  • Perkins GA
  • Worby CA
  • Engel JL
  • Heacock P
  • Nguyen OK
  • Wang JH
  • Raetz CR
  • Dowhan W
  • Dixon JE

Journal

Cell metabolism

Publication Data

June 8, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK054441
  • Agency: NIDDK NIH HHS, Id: DK18024
  • Agency: NIDDK NIH HHS, Id: DK18849
  • Agency: NIGMS NIH HHS, Id: GM069338
  • Agency: NIGMS NIH HHS, Id: GM56389
  • Agency: NIDDK NIH HHS, Id: P01 DK054441
  • Agency: NIDDK NIH HHS, Id: P01 DK054441-04
  • Agency: NCRR NIH HHS, Id: P41 RR004050
  • Agency: NCRR NIH HHS, Id: P41 RR004050-16
  • Agency: NIDDK NIH HHS, Id: R01 DK018849
  • Agency: NIDDK NIH HHS, Id: R01 DK018849-31
  • Agency: NIGMS NIH HHS, Id: R01 GM056389
  • Agency: NIGMS NIH HHS, Id: R01 GM056389-05
  • Agency: NIDDK NIH HHS, Id: R37 DK018024
  • Agency: NIDDK NIH HHS, Id: R37 DK018024-31
  • Agency: NCRR NIH HHS, Id: RR04050
  • Agency: NIGMS NIH HHS, Id: U54 GM069338
  • Agency: NIGMS NIH HHS, Id: U54 GM069338-07

Mesh Terms

  • Adenosine Triphosphate
  • Animals
  • Cardiolipins
  • Cell Line
  • Cell Respiration
  • Cloning, Molecular
  • Embryo, Mammalian
  • Genetic Engineering
  • Genotype
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Mitochondrial Membranes
  • Mutagenesis, Site-Directed
  • Mutation
  • PTEN Phosphohydrolase
  • Phosphatidylglycerols
  • Phosphoric Monoester Hydrolases
  • Recombinant Proteins
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins