DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress

• Published in: Biochimica et biophysica acta Vol. 1857; no. 8; pp. 1267 - 1276
• Main Authors: Oettinghaus, Björn, D'Alonzo, Donato, Barbieri, Elisa, Restelli, Lisa Michelle, Savoia, Claudia, Licci, Maria, Tolnay, Markus, Frank, Stephan, Scorrano, Luca
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-08-2016
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosome; Apoptotic Protease-Activating Factor 1 - deficiency; Apoptotic Protease-Activating Factor 1 - genetics; Bax/Bak; bcl-2 Homologous Antagonist-Killer Protein - deficiency; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2-Associated X Protein - deficiency; bcl-2-Associated X Protein - genetics; BH3 Interacting Domain Death Agonist Protein - genetics; BH3 Interacting Domain Death Agonist Protein - metabolism; Cell Line; Cristae remodeling; Cytochrome c release; Cytochromes c - secretion; Dynamins - deficiency; Dynamins - genetics; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Regulation; Hydrogen Peroxide - pharmacology; Mice; Mice, Knockout; Mitochondrial Dynamics - drug effects; Mitochondrial Dynamics - genetics; Mitochondrial fission; Oxidative Stress; Signal Transduction; Staurosporine - pharmacology; Thapsigargin - pharmacology; Bcl-2; MEFs; MOMP; Bax/Bak; IMM; DKO; Apoptosome; ER; Mitochondrial fission; OMM; Drp1; STS; TG; MFN; OPA1; Apaf1; Cristae remodeling; Cytochrome c release; wt; Apoptosis
• ISSN: 0005-2728; 0006-3002; 1879-2650
• DOI: 10.1016/j.bbabio.2016.03.016

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, H2O2, staurosporine and thapsigargin, Drp1−/− MEFs were protected only from BID and H2O2. 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.
•During apoptosis by intrinsic stimuli mitochondrial fission occurs independently of Bax, Bak and Apaf1.•Lack of Drp1 delays death induced by some but not all intrinsic stimuli.•Mitochondrial fragmentation during apoptosis occurs also in Drp1 deficient cells.•Lack of Drp1 reduces cristae remodeling and intramitochondrial cytochrome c redistribution.