Differential Activation of Pro-Survival Pathways by NIX/BNIP3L: An Expression-Level-Dependent Mechanism Governing PC12 Cell Fate During H2O2-Induced Oxidative Stress

Oxidative stress is a major contributor to neuronal apoptosis and subsequent neurofunctional deficits. This study investigates the dual role of the mitochondrial membrane-anchored protein NIX in PC12 cells, a model for mature neurons. We demonstrate that both overexpression and knockdown of NIX attenuate apoptosis under oxidative stress, albeit through distinct mechanisms. Overexpression of NIX promotes cell survival by activating NIX-mediated mitophagy, which clears damaged mitochondria and intracellular reactive oxygen species (ROS), thereby maintaining redox homeostasis. Conversely, knockdown of NIX reduces apoptosis primarily by diminishing the intrinsic pro-apoptotic function of the protein. Collectively, these findings reveal that NIX expression levels critically gate PC12 cell fate under oxidative stress by differentially activating pro-survival or anti-apoptotic pathways.