title: MAPL SUMOylation of Drp1 Stabilizes an ER/Mitochondrial Platform Required for Cell Death.
abstract: There has been evidence that mitochondrial fragmentation is required for apoptosis, but the molecular links between the machinery regulating dynamics and cell death have been controversial. Indeed, activated BAX and BAK can form functional channels in liposomes, bringing into question the contribution of mitochondrial dynamics in apoptosis. We now demonstrate that the activation of apoptosis triggers MAPL/MUL1-dependent SUMOylation of the fission GTPase Drp1, a process requisite for cytochrome c release. SUMOylated Drp1 functionally stabilizes ER/mitochondrial contact sites that act as hotspots for mitochondrial constriction, calcium flux, cristae remodeling, and cytochrome c release. The loss of MAPL does not alter the activation and assembly of BAX/BAK oligomers, indicating that MAPL is activated downstream of BAX/BAK. This work demonstrates how interorganellar contacts are dynamically regulated through active SUMOylation during apoptosis, creating a stabilized platform that signals cytochrome c release.
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Ave, Montreal, QC H3A 2B4, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Prudent
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Ave, Montreal, QC H3A 2B4, Canada.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Zunino
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Ave, Montreal, QC H3A 2B4, Canada.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Sugiura
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Ave, Montreal, QC H3A 2B4, Canada.
authors.forename: Sevan
authors.initials: S
authors.lastname: Mattie
authors.affiliation: McIntyre Medical Sciences Building, Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Ave, Montreal, QC H3A 2B4, Canada. Electronic address: heidi.mcbride@mcgill.ca.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: McBride
mesh_terms: D017209:Apoptosis; D020013:Calcium Signaling; D003546:Cysteine Endopeptidases / Q000378:metabolism; D034281:Dynamins; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C529067:MUL1 protein, human; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; C512579:Senp5 protein, human; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: BAX/BAK; Drp1; MAPL; MUL1; SUMO; SenP5; apoptosis; mitochondria; mitochondria/ER contact sites