Genetic ablation and short-duration inhibition of lipoxygenase results in increased macroautophagy

• A relationship between lipoxygenases and autophagy is disclosed.
• 12/15-lipoxygenase knockout increases autophagy in mice liver and brain.
• Lipoxygenase inhibition boosts autophagy in human hepatoma and neuroblastoma cells.
• Lipoxygenase knockout or inhibition triggers selective autophagy.

12/15-lipoxygenase (12/15-LOX) is involved in organelle homeostasis by degrading mitochondria in maturing red blood cells and by eliminating excess peroxisomes in liver. Furthermore, 12/15-LOX contributes to diseases by exacerbating oxidative stress-related injury, notably in stroke. Nonetheless, it is unclear what the consequences are of abolishing 12/15-LOX activity. Mice in which the alox15 gene has been ablated do not show an obvious phenotype, and LOX enzyme inhibition is not overtly detrimental. We show here that liver histology is also unremarkable. However, electron microscopy demonstrated that 12/15-LOX knockout surprisingly leads to increased macroautophagy in the liver. Not only macroautophagy but also mitophagy and pexophagy were increased in hepatocytes, which otherwise showed unaltered fine structure and organelle morphology. These findings were substantiated by immunofluorescence showing significantly increased number of LC3 puncta and by Wes