Sequestration of the polyunsaturated fatty acids protects the cells with oxidative phosphorylation deficiency from 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. We identified 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). Here, we demonstrate that this mechanism represents a physiologically relevant protective strategy, manifesting in the cells under hypoxia and fibroblasts derived from patients with primary mitochondrial complex IV deficiency. As proof of principle, we observed 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. HighlightsO_LIOXPHOS-deficient cells trigger polyunsaturated fatty acid (PUFA) stress response that includes sequestration of PUFAs to TGs, downregulation of desaturases, and upregulation of lipid peroxide detoxification C_LIO_LIPUFA trafficking to TGs stored in lipid droplets protects the cells against lipid peroxidation and ferroptosis C_LIO_LIOXPHOS-deficient cells synthesise fatty acids de novo from glutamine-derived acetyl-CoA when reductive carboxylation is permissible C_LIO_LIPUFA stress response is activated in patients with mitochondrial deficiencies and during hypoxia C_LI