title: The ARL2 GTPase is required for mitochondrial morphology, motility, and maintenance of ATP levels.
abstract: ARF-like 2 (ARL2) is a member of the ARF family and RAS superfamily of regulatory GTPases, predicted to be present in the last eukaryotic common ancestor, and essential in a number of model genetic systems. Though best studied as a regulator of tubulin folding, we previously demonstrated that ARL2 partially localizes to mitochondria. Here, we show that ARL2 is essential to a number of mitochondrial functions, including mitochondrial morphology, motility, and maintenance of ATP levels. We compare phenotypes resulting from ARL2 depletion and expression of dominant negative mutants and use these to demonstrate that the mitochondrial roles of ARL2 are distinct from its roles in tubulin folding. Testing of current models for ARL2 actions at mitochondria failed to support them. Rather, we found that knockdown of the ARL2 GTPase activating protein (GAP) ELMOD2 phenocopies two of three phenotypes of ARL2 siRNA, making it a likely effector for these actions. These results add new layers of complexity to ARL2 signaling, highlighting the need to deconvolve these different cell functions. We hypothesize that ARL2 plays essential roles inside mitochondria along with other cellular functions, at least in part to provide coupling of regulation between these essential cell processes.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Newman
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Cheng-jing
authors.initials: CJ
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Samatha
authors.initials: S
authors.lastname: Mudigonda
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Alexa L
authors.initials: AL
authors.lastname: Mattheyses
authors.affiliation: Consiglio Nazionale delle Ricerche Institute of Biomembranes and Bioenergetics, Bari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Paradies
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Carlo Marya Thomas
authors.initials: CM
authors.lastname: Marobbio
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kahn
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D033741:Adenine Nucleotide Translocator 1 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors
chemical_list: C485676:ARL2BP protein, human; D033741:Adenine Nucleotide Translocator 1; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C512339:ELMOD2 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000255:Adenosine Triphosphate; C410130:ARL2 protein, human; D019204:GTP-Binding Proteins; D020727:ADP-Ribosylation Factors; C490247:ARL3 protein, human