Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Disorders: A Systems Biology Approach

Abstract

Mitochondrial dysfunction and oxidative stress represent two interlinked pathological mechanisms that play pivotal roles in the onset and progression of major neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Mitochondria, as the primary source of cellular energy, are central to neuronal survival, yet their impaired function leads to energy deficits, calcium dysregulation, and excessive generation of reactive oxygen species (ROS), which collectively disrupt neuronal homeostasis. ROS, while essential in low concentrations for physiological signaling, become detrimental when their production overwhelms antioxidant defense systems, thereby inducing oxidative damage to lipids, proteins, and nucleic acids. This pathological imbalance not only accelerates protein misfolding and aggregation but also initiates apoptotic signaling cascades that culminate in progressive neuronal cell death. In this study, a systems biology approach is employed to capture the complexity of mitochondrial dysfunction and oxidative stress by integrating multi-omics datasets with computational network modeling. The proposed framework enables the identification of critical regulatory hubs, such as Nrf2, SOD2, and PGC-1α, that govern redox homeostasis and mitochondrial biogenesis. Comparative analysis across multiple neurodegenerative conditions highlights both shared and disease-specific pathways, underscoring the potential for precision medicine strategies. Furthermore, the study evaluates therapeutic candidates, including mitochondria-targeted antioxidants, sirtuin modulators, and metabolic reprogramming agents, that can restore cellular redox balance and improve mitochondrial performance. The findings provide mechanistic insights into how mitochondrial dysfunction and oxidative stress synergistically contribute to neurodegeneration, while also offering a predictive framework for the discovery of novel therapeutic targets. Ultimately, this work advances our understanding of the molecular underpinnings of neurodegenerative diseases and demonstrates the power of systems biology in unravelling complex biological networks, thereby paving the way for translational applications in biomarker discovery and personalized therapeutic interventions.