The abundance of the ARL2 GTPase and its GAP, ELMOD2, at mitochondria are modulated by the fusogenic activity of mitofusins and stressors.

• Type of Material: Article
• Authors: Laura E. Newman, Emory University; Cara R. Schiavon, Emory University; Chengjing Zhou, Emory University; Richard Kahn, Emory University
• Language: English
• Date: 2017-04-05
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Newman et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0175164
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 12
• Issue: 4
• Start Page: e0175164
• End Page: e0175164
• Grant/Funding Information: National Institute of Neurological Disorders and Stroke P30NS055077.; American Heart Association 14PRE18840040 to Laura E. Newman.; National Institute of General Medical Sciences 5R01GM090158 to Richard A. Kahn.; Support was provided by the National Institutes of Health [https://www.nih.gov/] P30NS055077, 5R01GM090158 to RAK, 1F31GM111047 to LEN; and the American Heart Association [http://www.heart.org/HEARTORG/] 14PRE18840040 to LEN.; National Institute of General Medical Sciences 1F31GM111047 to Laura E. Newman.
• Keywords: Mitochondria; HeLa cells; Cellular stress responses; Guanosine triphosphatase; Cell fusion; Immunoblotting; Glucose; Cell staining
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

Mitochondria are essential, dynamic organelles that respond to a number of stressors with changes in morphology that are linked to several mitochondrial functions, though the mechanisms involved are poorly understood. We show that the levels of the regulatory GTPase ARL2 and its GAP, ELMOD2, are specifically increased at mitochondria in immortalized mouse embryo fibroblasts deleted for Mitofusin 2 (MFN2), but not MFN1. Elevated ARL2 and ELMOD2 in MEFs deleted for MFN2 could be reversed by re-introduction of MFN2, but only when the mitochondrial fragmentation in these MEFs was also reversed, demonstrating that reversal of elevated ARL2 and ELMOD2 requires the fusogenic activity of MFN2. Other stressors with links to mitochondrial morphology were investigated and several, including glucose or serum deprivation, also caused increases in ARL2 and ELMOD2. In contrast, a number of pharmacological inhibitors of energy metabolism caused increases in ARL2 without affecting ELMOD2 levels. Together we interpret these data as evidence of two ARL2-sensitive pathways in mitochondria, one affecting ATP levels that is independent of ELMOD2 and the other leading to mitochondrial fusion involving MFN2 that does involve ELMOD2.