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

• Type of Material: Article
• Authors: Cara R. Schiavon, Emory University; Rachel E. Turn, Emory University; Laura E. Newman, Salk Institute for Biological Studies; Richard A Kahn, Emory University
• Language: English
• Date: 2019-05-01
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Schiavon, Turn, et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E18-12-0804
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 30
• Issue: 10
• Start Page: 1198
• End Page: 1213
• Grant/Funding Information: This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities Grant 5P30NS055077.; We thank Neil Anthony (Emory University) for assistance with image quantification; as well as Christopher Ott, Geoff Daniels, and Gary Schools (Leica Microsystems) for assistance with acquisition and deconvolution of gSTED images.; This work was supported by NIH Grants R35GM122568 to R.A.K.; and 1F31GM111047 to L.E.N.
• Keywords: Life Sciences & Biomedicine; MAMMALIAN HOMOLOGS; DEGRADATION; BINDING; FISSION; TRANSPORT; ACTIVATION; PROTEIN; DYNAMICS; GTPASE ARL2; MITOPLD; Science & Technology; Cell Biology
• Research Categories: Biology, Cell; Chemistry, Biochemistry

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.