RT Journal Article
SR Electronic
T1 Autolysosomal exocytosis of lipids protect neurons from ferroptosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.24.517842
DO 10.1101/2022.11.24.517842
A1 Ralhan, Isha
A1 Chang, Jinlan
A1 Moulton, Matthew J.
A1 Goodman, Lindsey D.
A1 Lee, Nathanael Y.J.
A1 Plummer, Greg
A1 Pasolli, H. Amalia
A1 Matthies, Doreen
A1 Bellen, Hugo J.
A1 Ioannou, Maria S.
YR 2022
UL http://biorxiv.org/content/early/2022/11/24/2022.11.24.517842.abstract
AB 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.SUMMARY Release of lipid-protein particles by autolysosomal exocytosis protects neurons from ferroptosis.Competing Interest StatementThe authors have declared no competing interest.