Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis
Impaired energy production is a hallmark of mitochondrial oxidative phosphorylation (OXPHOS) defects. However, secondary metabolic disturbances also represent an important trigger for pathologies originating from OXPHOS aberrations. Here we show that cells with OXPHOS deficiencies accumulate triacylglycerols enriched in polyunsaturated fatty acids (PUFAs), which are stored in lipid droplets. Sequestration of PUFAs is a critical component of a broader stress response, which also includes downregulation of cellular desaturases and upregulation of glutathione peroxidase 4 (GPX4). We demonstrate that this mechanism represents a physiologically relevant protective strategy, manifesting in cells under hypoxia and in immortalised fibroblasts derived from patients with primary mitochondrial complex IV deficiency. As a proof of principle, we observe elevated PUFA-enriched triacylglycerols in the plasma of patients with Myoclonic Epilepsy with Ragged Red Fibres (MERRF). Our findings reveal a novel protective mechanism against ferroptosis, which preserves membrane integrity when mitochondrial respiration is compromised.
Authors
- Tomáš Mráček (ORCID: https://orcid.org/0000-0002-9492-0718)
- Michal Knězů (ORCID: https://orcid.org/0009-0007-6098-4426)
- Tomáš Čajka (ORCID: https://orcid.org/0000-0002-9728-3355)
- Ondřej Kuda (ORCID: https://orcid.org/0000-0001-7034-4536)
- Massimo Zeviani (ORCID: https://orcid.org/0000-0002-9067-5508)
- Lukáš Alán (ORCID: https://orcid.org/0000-0001-7417-2620)
- Erika Fernández‐Vizarra (ORCID: https://orcid.org/0000-0002-2469-142X)
- Petr Pecina (ORCID: https://orcid.org/0000-0003-0641-2834)
- Alena Pecinová (ORCID: https://orcid.org/0000-0002-0204-7502)
- Kristýna Čunátová (ORCID: https://orcid.org/0000-0001-9993-2040)
- Guillermo Puertas-Frias (ORCID: https://orcid.org/0000-0003-0580-3833)
- J Houštěk (ORCID: https://orcid.org/0000-0002-8413-4772)
- María José Saucedo-Rodríguez
- Patrik Hrbac
- Sona Konickova
- Jakub Schimmer
- Monika Krakovkova
- Tomáš Honzík
- Marek Vrbacký
- Hana Hansíková
Institutions
- Czech Academy of Sciences (CZ)
- Charles University (CZ)
- Universidad de Zaragoza (ES)
- IRCCS Materno Infantile Burlo Garofolo (IT)
- Institute of Microbiology (BY)
- BioEnergetics (United States) (US)
- Czech Academy of Sciences, Institute of Physiology (CZ)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-08-14
- DOI
- https://doi.org/10.1038/s44319-026-00898-y
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Univerzita Karlova v Praze
- Grantová Agentura, Univerzita Karlova
- European Commission
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Ministerstvo Zdravotnictví Ceské Republiky
- Akademie Věd České Republiky
- Agentura Pro Zdravotnický Výzkum České Republiky
- European Regional Development Fund