title: BID links ferroptosis to mitochondrial cell death pathways.
abstract: Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc-system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation. In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by Xc-inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6c9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Neitemeier
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Jelinek
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Laino
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Hoffmann
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Eisenbach
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Eying
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Goutham K
authors.initials: GK
authors.lastname: Ganjam
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Amalia M
authors.initials: AM
authors.lastname: Dolga
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Oppermann
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany. Electronic address: culmsee@staff.uni-marburg.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
mesh_terms: D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics* / Q000378:metabolism*; D064113:CRISPR-Cas Systems; D016923:Cell Death; D002460:Cell Line; D055786:Gene Knockout Techniques; D015227:Lipid Peroxidation; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D018384:Oxidative Stress; D010879:Piperazines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D010879:Piperazines; D017382:Reactive Oxygen Species; C477224:erastin
keywords: BID; CRISPR; Ferroptosis; Mitochondria; Neuronal death; Oxytosis