ELMOD2 regulates mitochondrial fusion in a mitofusin-dependent manner, downstream of ARL2

Mol Biol Cell. 2019 May 1;30(10):1198-1213. doi: 10.1091/mbc.E18-12-0804. Epub 2019 Mar 13.

Abstract

Mitochondria are essential and dynamic organelles undergoing constant fission and fusion. The primary players in mitochondrial morphology (MFN1/2, OPA1, DRP1) have been identified, but their mechanism(s) of regulation are still being elucidated. ARL2 is a regulatory GTPase that has previously been shown to play a role in the regulation of mitochondrial morphology. Here we demonstrate that ELMOD2, an ARL2 GTPase-activating protein (GAP), is necessary for ARL2 to promote mitochondrial elongation. We show that loss of ELMOD2 causes mitochondrial fragmentation and a lower rate of mitochondrial fusion, while ELMOD2 overexpression promotes mitochondrial tubulation and increases the rate of fusion in a mitofusin-dependent manner. We also show that a mutant of ELMOD2 lacking GAP activity is capable of promoting fusion, suggesting that ELMOD2 does not need GAP activity to influence mitochondrial morphology. Finally, we show that ELMOD2, ARL2, Mitofusins 1 and 2, Miros 1 and 2, and mitochondrial phospholipase D (mitoPLD) all localize to discrete, regularly spaced puncta along mitochondria. These results suggest that ELMOD2 is functioning as an effector downstream of ARL2 and upstream of the mitofusins to promote mitochondrial fusion. Our data provide insights into the pathway by which mitochondrial fusion is regulated in the cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism*
  • GTP Phosphohydrolases / metabolism
  • GTP-Binding Proteins / genetics*
  • GTP-Binding Proteins / metabolism*
  • Gene Knockout Techniques / methods
  • Humans
  • Membrane Fusion / physiology
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Mitochondrial Dynamics / physiology*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Phospholipase D / genetics
  • Phospholipase D / metabolism

Substances

  • Cytoskeletal Proteins
  • ELMOD2 protein, human
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Phospholipase D
  • mitoPLD protein, human
  • ARL2 protein, human
  • GTP Phosphohydrolases
  • GTP-Binding Proteins