title: Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of California-San Diego, La Jolla, CA 92093, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Wiley
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Worby
authors.forename: James L
authors.initials: JL
authors.lastname: Engel
authors.forename: Philip
authors.initials: P
authors.lastname: Heacock
authors.forename: Oanh Kim
authors.initials: OK
authors.lastname: Nguyen
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Wang
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: William
authors.initials: W
authors.lastname: Dowhan
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002308:Cardiolipins / Q000096:biosynthesis*; D002460:Cell Line; D019069:Cell Respiration / Q000235:genetics; D003001:Cloning, Molecular; D004622:Embryo, Mammalian / Q000378:metabolism; D005818:Genetic Engineering; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010715:Phosphatidylglycerols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases
chemical_list: D000255:Adenosine Triphosphate; D002308:Cardiolipins; D051059:PTEN Phosphohydrolase; D010715:Phosphatidylglycerols; D010744:Phosphoric Monoester Hydrolases; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C034358:phosphatidylglycerophosphate; C492433:Ptpmt1 protein, mouse; D017027:Protein Tyrosine Phosphatases; C026991:phosphatidylglycerophosphatase