Redox-Mitochondrial Crosstalk in Neurotoxicity: Regulated Cell Death Pathways and Neuroprotective Strategies.

Abstract

Neurotoxicity refers to injury of the central or peripheral nervous system caused by harmful stimuli including environmental chemicals, disease-associated endogenous stressors and other exposures that disturb neuronal homeostasis. A common outcome of neurotoxic stress is progressive disruption of synaptic function, redox balance and energy metabolism which together increase vulnerability to regulated cell-death programs. This review focuses on oxidative stress as core driver that shift reactive species from physiological signalling to direct chemical damage of lipids, proteins and DNA with mitochondria acting as a key integration point where oxidative damage and calcium dysregulation converge. We describe how mitochondrial dysfunction lowers the threshold for intrinsic apoptosis and how oxidative stress can also engage additional regulated death pathways relevant to neurotoxicity, including necroptosis, ferroptosis and parthanatos alongside ER stress and excitotoxicity that amplify the damage. Particular emphasis is placed on aging as a modifier of mitochondrial resilience and on the reciprocal interactions between disease-associated proteins, mitochondrial dysfunction and synaptic injury in major age-related neurodegenerative disorders. Finally, the review links these mechanisms to neurodegenerative diseases, acute neural injuries and environmental or chemical neurotoxins and summarizes neuroprotective strategies that target redox imbalance, mitochondrial stability and apoptosis-related signalling.