A mitochondrial phosphatase required for cardiolipin biosynthesis: the PGP phosphatase Gep4

EMBO J. 2010 Jun 16;29(12):1976-87. doi: 10.1038/emboj.2010.98. Epub 2010 May 18.


Cardiolipin (CL), a unique dimeric phosphoglycerolipid predominantly present in mitochondrial membranes, has pivotal functions for the cellular energy metabolism, mitochondrial dynamics and the initiation of apoptotic pathways. Perturbations in the mitochondrial CL metabolism cause cardiomyopathy in Barth syndrome. Here, we identify a novel phosphatase in the mitochondrial matrix space, Gep4, and demonstrate that it dephosphorylates phosphatidylglycerolphosphate to generate phosphatidylglycerol, an essential step during CL biosynthesis. Expression of a mitochondrially targeted variant of Escherichia coli phosphatase PgpA restores CL levels in Gep4-deficient cells, indicating functional conservation. A genetic epistasis analysis combined with the identification of intermediates of CL biosynthesis allowed us to integrate Gep4 in the CL-biosynthetic pathway and assign an essential function during early steps of CL synthesis to Tam41, which has previously been shown to be essential for the maintenance of normal CL levels. Our experiments provide the framework for the further dissection of mechanisms that are required for accumulation and maintenance of CL levels in mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Biosynthetic Pathways / genetics
  • Cardiolipins / biosynthesis*
  • Escherichia coli Proteins / genetics
  • Genes, Essential
  • Mitochondria / enzymology*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Organisms, Genetically Modified
  • Phosphatidylglycerols / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Saccharomyces cerevisiae / physiology*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism


  • Cardiolipins
  • Escherichia coli Proteins
  • Mitochondrial Proteins
  • Phosphatidylglycerols
  • Saccharomyces cerevisiae Proteins
  • TAM41 protein, S cerevisiae
  • phosphatidylglycerophosphate
  • Phosphoric Monoester Hydrolases
  • phosphatidylglycerophosphatase