Sar1, a Novel Regulator of ER-Mitochondrial Contact Sites

PLoS One. 2016 Apr 21;11(4):e0154280. doi: 10.1371/journal.pone.0154280. eCollection 2016.

Abstract

Endoplasmic reticulum (ER)-mitochondrial contact sites play a pivotal role in exchange of lipids and ions between the two organelles. How size and function of these contact sites are regulated remains elusive. Here we report a previously unanticipated, but conserved role of the small GTPase Sar1 in the regulation of ER-mitochondrial contact site size. Activated Sar1 introduces membrane curvature through its N-terminal amphiphatic helix at the ER-mitochondria interphase and thereby reducing contact size. Conversely, the S. cerevisiae N3-Sar1 mutant, in which curvature induction is decreased, caused an increase in ER-mitochondrial contacts. As a consequence, ER tubules are no longer able to mark the prospective scission site on mitochondria, thereby impairing mitochondrial dynamics. Consistently, blocking mitochondrial fusion partially rescued, whereas deletion of the dynamin-like protein enhanced the phenotype in the sar1D32G mutant. We conclude that Sar1 regulates the size of ER-mitochondria contact sites through its effects on membrane curvature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Conserved Sequence
  • Dynamins / genetics
  • Dynamins / metabolism
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • GTP Phosphohydrolases / antagonists & inhibitors
  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Intracellular Membranes / chemistry
  • Intracellular Membranes / metabolism
  • Ion Transport
  • Lipid Metabolism
  • Mitochondria / chemistry
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics
  • Monomeric GTP-Binding Proteins / antagonists & inhibitors
  • Monomeric GTP-Binding Proteins / genetics*
  • Monomeric GTP-Binding Proteins / metabolism
  • Mutation
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae / ultrastructure
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction
  • Vesicular Transport Proteins / antagonists & inhibitors
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • RNA, Small Interfering
  • Saccharomyces cerevisiae Proteins
  • Vesicular Transport Proteins
  • GTP Phosphohydrolases
  • SAR-1 protein, C elegans
  • SAR1A protein, human
  • Monomeric GTP-Binding Proteins
  • SAR1 protein, S cerevisiae
  • Dynamins
  • dynamin-related protein 1, C elegans

Grants and funding

This work was supported by the University of Basel: unibas.ch, and Swiss National Science Foundation: 31003A_141207, snf.ch. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.