Mitochondria-type GPAT is required for mitochondrial fusion

EMBO J. 2013 May 2;32(9):1265-79. doi: 10.1038/emboj.2013.77. Epub 2013 Apr 9.

Abstract

Glycerol-3-phosphate acyltransferase (GPAT) is involved in the first step in glycerolipid synthesis and is localized in both the endoplasmic reticulum (ER) and mitochondria. To clarify the functional differences between ER-GPAT and mitochondrial (Mt)-GPAT, we generated both GPAT mutants in C. elegans and demonstrated that Mt-GPAT is essential for mitochondrial fusion. Mutation of Mt-GPAT caused excessive mitochondrial fragmentation. The defect was rescued by injection of lysophosphatidic acid (LPA), a direct product of GPAT, and by inhibition of LPA acyltransferase, both of which lead to accumulation of LPA in the cells. Mitochondrial fragmentation in Mt-GPAT mutants was also rescued by inhibition of mitochondrial fission protein DRP-1 and by overexpression of mitochondrial fusion protein FZO-1/mitofusin, suggesting that the fusion/fission balance is affected by Mt-GPAT depletion. Mitochondrial fragmentation was also observed in Mt-GPAT-depleted HeLa cells. A mitochondrial fusion assay using HeLa cells revealed that Mt-GPAT depletion impaired mitochondrial fusion process. We postulate from these results that LPA produced by Mt-GPAT functions not only as a precursor for glycerolipid synthesis but also as an essential factor of mitochondrial fusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Caenorhabditis elegans Proteins / physiology
  • Female
  • Gene Deletion
  • Glycerol-3-Phosphate O-Acyltransferase / genetics
  • Glycerol-3-Phosphate O-Acyltransferase / metabolism*
  • Glycerol-3-Phosphate O-Acyltransferase / physiology
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology
  • Microsomes / metabolism
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Mitochondria / genetics
  • Mitochondrial Dynamics*
  • Mitochondrial Size / drug effects
  • Mitochondrial Size / genetics
  • Models, Biological
  • Mutagenesis, Site-Directed
  • Oogenesis / genetics

Substances

  • Caenorhabditis elegans Proteins
  • Lysophospholipids
  • Acl-6 protein, C elegans
  • Glycerol-3-Phosphate O-Acyltransferase
  • lysophosphatidic acid