While impaired energy production is a hallmark of mitochondrial oxidative phosphorylation (OXPHOS) defects, many OXPHOS aberrations permit residual energy output, leading to pathologies driven by secondary metabolic disturbances, such as redox stress. We have discovered 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.