title: DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress.
abstract: During apoptosis mitochondria undergo cristae remodeling and fragmentation, but how the latter relates to outer membrane permeabilization and downstream caspase activation is unclear. Here we show that the mitochondrial fission protein Dynamin Related Protein (Drp) 1 participates in cytochrome c release by selected intrinsic death stimuli. While Bax, Bak double deficient (DKO) and Apaf1(-/-) mouse embryonic fibroblasts (MEFs) were less susceptible to apoptosis by Bcl-2 family member BID, H(2)O(2), staurosporine and thapsigargin, Drp1(-/-) MEFs were protected only from BID and H(2)O(2). Resistance to cell death of Drp1(-/-) and DKO MEFs correlated with blunted cytochrome c release, whereas mitochondrial fragmentation occurred in all cell lines in response to all tested stimuli, indicating that other mechanisms accounted for the reduced cytochrome c release. Indeed, cristae remodeling was reduced in Drp1(-/-) cells, potentially explaining their resistance to apoptosis. Our results indicate that caspase-independent mitochondrial fission and Drp1-dependent cristae remodeling amplify apoptosis. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland.
authors.forename: Björn
authors.initials: B
authors.lastname: Oettinghaus
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland.
authors.forename: Donato
authors.initials: D
authors.lastname: D'Alonzo
authors.affiliation: Department of Biology, University of Padua, Via U Bassi 58B, 35121 Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barbieri
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland.
authors.forename: Lisa Michelle
authors.initials: LM
authors.lastname: Restelli
authors.affiliation: Department of Biology, University of Padua, Via U Bassi 58B, 35121 Padua, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Savoia
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland; Department of Neurosurgery, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Licci
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Tolnay
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland. Electronic address: stephan.frank@usb.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.affiliation: Department of Biology, University of Padua, Via U Bassi 58B, 35121 Padua, Italy; Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padua, Italy. Electronic address: luca.scorrano@unipd.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1 / Q000172:deficiency / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins / Q000172:deficiency / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics*; D018384:Oxidative Stress; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019284:Thapsigargin; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C486391:Dnm1l protein, mouse; D034281:Dynamins; D019311:Staurosporine
keywords: Apoptosis; Apoptosome; Bax/Bak; Cristae remodeling; Cytochrome c release; Mitochondrial fission