title: Proteasomes associated with the Blm10 activator protein antagonize mitochondrial fission through degradation of the fission protein Dnm1.
abstract: The conserved Blm10/PA200 activators bind to the proteasome core particle gate and facilitate turnover of peptides and unfolded proteins in vitro. We report here that Blm10 is required for the maintenance of functional mitochondria. BLM10 expression is induced 25-fold upon a switch from fermentation to oxidative metabolism. In the absence of BLM10, Saccharomyces cerevisiae cells exhibit a temperature-sensitive growth defect under oxidative growth conditions and produce colonies with dysfunctional mitochondria at high frequency. Loss of BLM10 leads to reduced respiratory capacity, increased mitochondrial oxidative damage, and reduced viability in the presence of oxidative stress or death stimuli. In the absence of BLM10, increased fragmentation of the mitochondrial network under oxidative stress is observed indicative of elevated activity of the mitochondrial fission machinery. The degradation of Dnm1, the main factor mediating mitochondrial fission, is impaired in the absence of BLM10 in vitro and in vivo. These data suggest that the mitochondrial functional and morphological changes observed are related to elevated Dnm1 levels. This hypothesis is supported by the finding that cells that constitutively overexpress DNM1 display the same mitochondrial defects as blm10Δ cells. The data are consistent with a model in which Blm10 proteasome-mediated turnover of Dnm1 is required for the maintenance of mitochondrial function and provides cytoprotection under conditions that induce increased mitochondrial damage and programmed cell death.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Tar
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dange
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Ciyu
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Yao
authors.affiliation: INSERM, Institute Cochin, 24 Rue du Faubourg Saint Jacques, 75014 Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bulteau
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Elena Fernandez
authors.initials: EF
authors.lastname: Salcedo
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Stephen
authors.initials: S
authors.lastname: Braigen
authors.affiliation: INSERM, Institute Cochin, 24 Rue du Faubourg Saint Jacques, 75014 Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bouillaud
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 10115.
authors.forename: Daniel
authors.initials: D
authors.lastname: Finley
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461. Electronic address: marion.schmidt@einstein.yu.edu.
authors.forename: Marion
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C500597:Blm10 protein, S cerevisiae; D017931:DNA Primers; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; C094774:DNM1 protein, S cerevisiae
keywords: Mitochondria; Oxidative Stress; Proteasome; Protein Degradation; Respiration