Autolysosomal exocytosis of lipids protect neurons from ferroptosis

Abstract

During oxidative stress neurons release lipids that are internalized by glia. Defects in this coordinated process play an important role in several neurodegenerative diseases. Yet, the mechanisms of lipid release and its consequences on neuronal health are unclear. Here, we demonstrate that lipid-protein particle release by autolysosome exocytosis protects neurons from ferroptosis, a form of cell death driven by lipid peroxidation. We show that during oxidative stress, peroxidated lipids and iron are released from neurons by autolysosomal exocytosis which requires the exocytic machinery; VAMP7 and syntaxin 4. We observe membrane-bound lipid-protein particles by TEM and demonstrate that these particles are released from neurons using cryoEM. Failure to release these lipid-protein particles causes lipid hydroperoxide and iron accumulation and sensitizes neurons to ferroptosis. Our results reveal how neurons protect themselves from peroxidated lipids. Given the number of brain pathologies that involve ferroptosis, defects in this pathway likely play a key role in the pathophysiology of neurodegenerative disease.

Neuronal lysosome transfer to oligodendrocyte precursor cells: a novel mechanism of neuron-glia communication and its role in neurodegenerative diseases

“…When neurons are active, they increase their metabolic rate 34 , resulting in the generation of more 'waste' products that need to be transported out of the cell. Failure to effectively export and clear this waste could subject neurons to stress, ferroptosis or degeneration, as seen in lysosomal storage diseases [35][36][37] . Therefore, having a helper cell capable of cleaning up this 'waste' while remaining sustainably available in the brain becomes essential.…”

Ferroptotic therapy in cancer: benefits, side effects, and risks

“…This essential process, involved in the transport and secretion of diverse molecules, including proteins, lipids, neurotransmitters, and hormones, plays a protective role. It particularly safeguards neurons from ferroptosis by facilitating the release of lipids and iron from autolysosomes [144].…”