Neuronal ferroptosis and lipid reprograming

SALVADOR GABRIELA

Buenos Aires

Simposio; Redox Biology- Satellite meeting SRBMB; 2023

Grupu Sudamericano Redox Biology

Lipid reprogramming in neuronal ferroptosisGabriela A. SalvadorInstituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB)-CONICETDepartamento de Biología, Bioquímica y Farmacia - Universidad Nacional del Sur (UNS)Iron accumulation and α-synuclein aggregation are neurotoxic factors associated with ferroptosis in dopaminergic neurons. The loss of dopaminergic neurons in midbrain is a pathognomonic sign of Parkinson´s disease. We found that neuronal challenge with the above-mentioned neurotoxicants triggers neutral lipid disturbances. Depending on neuronal injury level, lipid droplet increase can act as either protective against damage or as a promoter of cellular death. In addition, Maneb, a ferroptosis inducer associated with Parkinsonism, triggers an imbalance in arachidonic acid (AA) and docosahexaenoic acid (DHA) content both in neurons and astrocytes. As a response to Maneb challenge, neurons and astrocytes are able to activate AA- and DHA-dependent resolution pathways to mitigate pro-inflammatory signaling and promote cell survival. The inflammation/resolution balance is governed by a plethora of specialized pro-resolving lipid mediators that act as ligands of the GPCR receptor FPR2/ALX. Pro-resolving lipid mediators are mainly synthetized by lipoxygenases from AA and DHA. We also demonstrated that neurons and astrocytes secrete lipid ligands for FPR2/ALX-mediated resolution in response to Maneb toxicity. However, lipolysis and free cholesterol accumulation are associated with massive midbrain neuronal death and ferroptosis under severe injury conditions, matching with movement disorders in animal models. Our results lead us to hypothesize that lipid droplets are ying/yang effectors of neurodegeneration as AA and DHA donors or sinks, working as dynamic organelles to intervene resolution or pro-inflammatory signaling.Keywords: neutral lipids, ferroptosis, specialized pro-resolving lipid mediators, neurotoxicityFunding: CONICET, ANPCyT, PGI-UNS