On murine N2a cells, 7-ketocholesterol induced an oxiapotophagic mode of cell death characterized by
oxidative stress (reactive oxygen species overproduction on whole cells and at the mitochondrial level;
lipid peroxidation), apoptosis induction (caspase-9, -3 and -7 cleavage, PARP degradation) and
autophagy (increased ratio LC3-II / LC3-I). Oxidative stress was strongly attenuated by
diphenyleneiodonium chloride which inhibits NAD(P)H oxidase. Mitochondrial and peroxisomal
morphological and functional changes were also observed. Down regulation of PDK1 / Akt signaling
pathways as well as of GSK3 / Mcl-1 and Nrf2 pathways were simultaneously observed in 7-
ketocholesterol-induced oxiapoptophagy. These events were prevented by α-linolenic acid,
eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol. The inhibition of the
cytoprotection by LY-294002, a PI3-K inhibitor, demonstrated an essential role of PI3-K in cell rescue.
The rupture of oxidative stress in 7-ketocholesterol-induced oxiapoptophagy was also associated with
important modifications of glutathione peroxidase, superoxide dismutase and catalase activities as well
as of glutathione peroxidase-1, superoxide dismutase-1 and catalase level and expression. These events
were also counteracted by α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and
α-tocopherol. The inhibition of the cytoprotection by mercaptosuccinic acid, a glutathione peroxidase
inhibitor, showed an essential role of this enzyme in cell rescue. Altogether, our data support that the
reactivation of PI3-K and glutathione peroxidase activities by α-linolenic acid, eicosapentaenoic acid,
docosahexaenoic acid, oleic acid and α-tocopherol are essential to prevent 7KC-induced
oxiapoptophagy.
Curr Res Toxicol., 2024, 2024 Feb 8;6:100153. doi: 10.1016/j.crtox.2024.100153