Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis

Ferroptosis is a form of oxidative cell death that characterized by enhanced lipid peroxidation and mitochondrial impairment. The enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) lysophosphatidylcholine acyltransferase (LPCAT) play an essential role in the biosynthesis polyunsaturated fatty acid (PUFA)-containing phospholipids, thereby providing substrates for promoting ferroptosis. To examine impact mitochondria ACSL4/LPCAT2-driven ferroptosis, HEK293T cells overexpressing ACSL4 LPCAT2 (OE) or empty vector controls (LV) were exposed to 1S, 3R-RSL3 (RSL3) induction ACSL4/LPCAT2 overexpression resulted higher sensitivity against RSL3-induced compared LV-transfected controls. Moreover, parameters such as reactive oxygen species (ROS) formation, membrane potential, respiration deteriorated OE cells, supporting conclusion significant This was further confirmed through protection RSL3-mediated ROS scavenger mitoquinone (MitoQ), which exerted via antioxidative properties rather than previously reported metabolic effects. Our findings implicate production accompanying organelle disintegration are mediating initiated