Universität zu Köln

Pedrera, Lohans ORCID: 0000-0003-3639-1480, Prieto Clemente, Laura, Dahlhaus, Alina ORCID: 0000-0001-9055-0695, Lotfipour Nasudivar, Sara, Tishina, Sofya ORCID: 0000-0002-8232-496X, Olmo González, Daniel, Stroh, Jenny, Yapici, Fatma Isil ORCID: 0009-0004-9298-8315, Singh, Randhwaj Pratap, Grotehans, Nils, Langer, Thomas ORCID: 0000-0003-1250-1462, García-Sáez, Ana J. ORCID: 0000-0002-3894-5945 and von Karstedt, Silvia ORCID: 0000-0002-7816-5919 (2025). Ferroptosis triggers mitochondrial fragmentation via Drp1 activation. Cell Death & Disease, 16 (1). pp. 1-12. Springer Nature. ISSN 2041-4889

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Abstract

Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Pedrera, Lohans UNSPECIFIED https://orcid.org/0000-0003-3639-1480 UNSPECIFIED Prieto Clemente, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahlhaus, Alina UNSPECIFIED https://orcid.org/0000-0001-9055-0695 UNSPECIFIED Lotfipour Nasudivar, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Tishina, Sofya UNSPECIFIED https://orcid.org/0000-0002-8232-496X UNSPECIFIED Olmo González, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroh, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Yapici, Fatma Isil UNSPECIFIED https://orcid.org/0009-0004-9298-8315 UNSPECIFIED Singh, Randhwaj Pratap UNSPECIFIED UNSPECIFIED UNSPECIFIED Grotehans, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED https://orcid.org/0000-0003-1250-1462 UNSPECIFIED García-Sáez, Ana J. UNSPECIFIED https://orcid.org/0000-0002-3894-5945 UNSPECIFIED von Karstedt, Silvia UNSPECIFIED https://orcid.org/0000-0002-7816-5919 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-792434
Identification Number:	10.1038/s41419-024-07312-2
Journal or Publication Title:	Cell Death & Disease
Volume:	16
Number:	1
Page Range:	pp. 1-12
Date:	25 January 2025
Publisher:	Springer Nature
ISSN:	2041-4889
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers External institution Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics Faculty of Medicine > Sonstiges > Translationale Genomik Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79243