title: Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission.
abstract: Cytosolic dynamin-related protein 1 (Drp1, also known as DNM1L) is required for both mitochondrial and peroxisomal fission. Drp1-dependent division of these organelles is facilitated by a number of adaptor proteins at mitochondrial and peroxisomal surfaces. To investigate the interplay of these adaptor proteins, we used gene-editing technology to create a suite of cell lines lacking the adaptors MiD49 (also known as MIEF2), MiD51 (also known as MIEF1), Mff and Fis1. Increased mitochondrial connectivity was observed following loss of individual adaptors, and this was further enhanced following the combined loss of MiD51 and Mff. Moreover, loss of adaptors also conferred increased resistance of cells to intrinsic apoptotic stimuli, with MiD49 and MiD51 showing the more prominent role. Using a proximity-based biotin labeling approach, we found close associations between MiD51, Mff and Drp1, but not Fis1. Furthermore, we found that MiD51 can suppress Mff-dependent enhancement of Drp1 GTPase activity. Our data indicates that Mff and MiD51 regulate Drp1 in specific ways to promote mitochondrial fission.
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Osellame
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
authors.forename: Abeer P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Stroud
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Palmer
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, 3010, Australia.
authors.forename: Diana
authors.initials: D
authors.lastname: Stojanovski
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramachandran
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia Michael.Ryan@monash.edu.
authors.forename: Michael T
authors.identifier: 0000-0003-2586-8829
authors.initials: MT
authors.lastname: Ryan
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D034281:Dynamins / Q000378:metabolism*; D000072669:Gene Editing; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020675:Peroxisomes / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013194:Staining and Labeling
chemical_list: C561064:FIS1 protein, mouse; C000608253:MIEF2 protein, mouse; D008565:Membrane Proteins; C000597830:MiD51 protein, mouse; D024101:Mitochondrial Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C000603499:mitochondrial fission factor, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Apoptosis; Dynamin-related protein 1; Fission; GTPase; Mitochondria