title: Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein.
abstract: Ubiquitin- and proteasome-dependent outer mitochondrial membrane (OMM)-associated degradation (OMMAD) is critical for mitochondrial and cellular homeostasis. However, the scope and molecular mechanisms of the OMMAD pathways are still not well understood. We report that the OMM-associated E3 ubiquitin ligase MARCH5 controls dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and cell sensitivity to stress-induced apoptosis. MARCH5 knockout selectively inhibited ubiquitination and proteasomal degradation of MiD49, a mitochondrial receptor of Drp1, and consequently led to mitochondrial fragmentation. Mitochondrial fragmentation in MARCH5(-/-) cells was not associated with inhibition of mitochondrial fusion or bioenergetic defects, supporting the possibility that MARCH5 is a negative regulator of mitochondrial fission. Both MARCH5 re-expression and MiD49 knockout in MARCH5(-/-) cells reversed mitochondrial fragmentation and reduced sensitivity to stress-induced apoptosis. These findings and data showing MARCH5-dependent degradation of MiD49 upon stress support the possibility that MARCH5 regulation of MiD49 is a novel mechanism controlling mitochondrial fission and, consequently, the cellular response to stress.
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Edward
authors.initials: E
authors.lastname: Cherok
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Shweta
authors.initials: S
authors.lastname: Das
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Sunan
authors.initials: S
authors.lastname: Li
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Anesthesiology and the Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Roelofs
authors.affiliation: Department of Anesthesiology and the Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Shealinna X
authors.initials: SX
authors.lastname: Ge
authors.affiliation: Department of Anesthesiology and the Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Polster
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Liron
authors.initials: L
authors.lastname: Boyman
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: W Jonathan
authors.initials: WJ
authors.lastname: Lederer
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Chunxin
authors.initials: C
authors.lastname: Wang
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201 mkarbowski@umaryland.edu.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
mesh_terms: D017209:Apoptosis / Q000502:physiology; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010445:Peptide Elongation Factors / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C585230:MIEF2 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D010445:Peptide Elongation Factors; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins