Oxidative Stress and Regulated Cell Death Mechanisms in Neuronal Systems

Oxidative stress arises when the generation of reactive oxygen species (ROS) overwhelms intrinsic antioxidant defences, leading to damage of proteins, lipids and nucleic acids. In neuronal systems, this imbalance is a critical contributor to the pathogenesis of disorders such as Alzheimer’s disease, Parkinson’s disease and stroke. Neurons are particularly vulnerable to oxidative insults because of their high metabolic demand, abundant polyunsaturated lipids and relatively low regenerative capacity. Regulated cell death pathways—including apoptosis, necroptosis and the non‐apoptotic programmes oxytosis and ferroptosis—are orchestrated via distinct molecular cascades that converge on membrane integrity and organelle function. Ferroptosis, characterised by iron‐dependent lipid peroxidation, has emerged as a key mechanism in neurodegeneration, while oxytosis shares many molecular features with ferroptosis but is initiated by glutathione depletion. Central to these processes are mitochondrial dysfunction and dysregulated calcium homeostasis, which amplify ROS production and trigger downstream death effectors. Understanding the interplay between oxidative insults and regulated cell death in neurons has opened avenues for therapeutic intervention, ranging from antioxidant strategies to modulation of lipid metabolism, iron chelation and stabilisation of mitochondrial function. Insights into these pathways offer the prospect of slowing or halting neuronal loss in a range of acute and chronic neurological conditions.

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Technical terms

Oxidative stress: An imbalance between ROS production and antioxidant capacity, leading to cellular damage.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen, including superoxide and hydrogen peroxide.

Ferroptosis: A regulated, iron‐dependent form of cell death driven by lipid peroxidation.

Oxytosis: A glutathione depletion‐induced cell death pathway sharing molecular features with ferroptosis.

Mitochondrial dysfunction: Impairment of mitochondrial respiratory chain or membrane potential that exacerbates ROS generation.

Lipid peroxidation: Oxidative degradation of polyunsaturated lipids, compromising membrane integrity.

Mitochondrial calcium uniporter (MCU): A transmembrane channel complex that mediates Ca2+ uptake into the mitochondrial matrix.

Hypoxia‐inducible factor 1 (HIF-1) pathway: A transcriptional programme activated under low oxygen or metabolic stress to promote cell survival.

References

1. Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis. Cell Death & Disease (2023).
2. Mitochondrial transplantation rescues neuronal cells from ferroptosis. Free Radical Biology and Medicine (2023).
3. Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway. iScience (2022).
4. Oxytosis/Ferroptosis—(Re-) Emerging Roles for Oxidative Stress-Dependent Non-apoptotic Cell Death in Diseases of the Central Nervous System. Frontiers in Neuroscience (2018).