How neurons cope with oxidative stress

Neurons are highly dependent on mitochondrial respiration for energy, rendering them vulnerable to oxidative stress. Reactive oxygen species (ROS), by-products of oxidative phosphorylation, can damage lipids, proteins, and DNA, potentially triggering cell death pathways. This review explores the neuronal vulnerability to ROS, highlighting metabolic adaptations and antioxidant systems that mitigate oxidative damage. Balancing metabolic needs and oxidative stress defenses is critical for neurons, as disruptions are implicated in neurodegenerative diseases. Neurons uniquely modulate metabolic pathways, favoring glycolysis over oxidative phosphorylation in cell bodies, to minimize harmful ROS production. Key antioxidants, including superoxide dismutases and glutathione peroxidases, play crucial roles in neuronal protection, as evident from genetic studies linking deficiencies to neurodegeneration. Notably, neurons have the ability to adapt to oxidative conditions in compartment-specific manners and also utilize ROS as a signaling molecule to promote adaptive synaptic plasticity. Future research should aim to elucidate differential ROS signaling and antioxidant responses across neuronal compartments for improved therapeutic strategies.