Lipid bilayer polyunsaturated fatty acids and lipid peroxyl radicals in cellular and mitochondrial membranes (PUFA/LOO•)

Polyunsaturated fatty acids (PUFAs) are essential structural components of cellular and mitochondrial membranes, where they maintain fluidity and serve as precursors for signaling molecules [1]. However, the presence of bis-allylic hydrogen atoms makes PUFAs highly susceptible to attack by reactive oxygen species, leading to the formation of lipid peroxyl radicals (LOO•) [1, 2]. These radicals initiate a self-propagating chain reaction of lipid peroxidation that severely damages membrane integrity and can trigger ferroptosis, a form of iron-dependent regulated cell death [2, 4]. This oxidative degradation is a hallmark of various pathological states, including neurodegenerative diseases like Parkinson's and Alzheimer's, as well as ischemia-reperfusion injury and certain cancers [1, 2]. Therapeutic strategies targeting these molecules include radical-trapping antioxidants (RTAs) such as Ferrostatin-1 and Liproxstatin-1, which scavenge peroxyl radicals to terminate the peroxidation chain [4]. Additionally, the use of deuterated PUFAs (e.g., RT-001) provides a novel approach by using the kinetic isotope effect to stabilize the bis-allylic positions against hydrogen abstraction, thereby preventing the initiation of the radical cascade [3]. By protecting the lipid bilayer from oxidative degradation, these interventions aim to preserve cellular viability and mitochondrial function under conditions of high oxidative stress [2, 4].

Other names

Membrane polyunsaturated fatty acidsLipid peroxyl radicalsLOO•Bis-allylic lipidsLipid hydroperoxidesMitochondrial membrane lipids

Radical trapping and neutralization of lipid peroxyl radicals to terminate peroxidation chains, and isotopic stabilization of bis-allylic positions to inhibit hydrogen abstraction.