The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy.
This focused review synthesizes how mitochondrial defects (bioenergetics, calcium handling, dynamics, mitophagy, ROS and mtDNA-mediated inflammation) drive neurodegeneration and evaluates mitochondria-targeted therapies—from antioxidants and mitochondrial transfer to lifestyle and…
What the AI sees
This focused review synthesizes how mitochondrial defects (bioenergetics, calcium handling, dynamics, mitophagy, ROS and mtDNA-mediated inflammation) drive neurodegeneration and evaluates mitochondria-targeted therapies—from antioxidants and mitochondrial transfer to lifestyle and…
Research significance
Highly relevant to Parkinson's therapeutic discovery because it consolidates actionable mitochondrial mechanisms and intervention strategies, highlights disease-stage and patient-heterogeneity issues, and therefore serves as a practical roadmap for prioritizing target-specific interventions and…
Source abstract
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, remain leading causes of disability and premature death. Although they present with distinct clinical phenotypes, they converge on several pathogenic processes. Among these, mitochondrial dysfunction has emerged as a key driver of neurodegeneration, encompassing impaired bioenergetic capacity, disturbed calcium handling, altered mitochondrial dynamics, insufficient mitophagy, and excessive production of reactive oxygen species (ROS). This review provides a focused synthesis of the ways in which mitochondrial pathology contributes to neurodegeneration across major neurodegenerative disorders and summarizes therapeutic strategies designed to target mitochondria. We outline disease-relevant mitochondrial abnormalities and connect them to neuronal loss, synaptic failure, and neuroinflammatory cascades, with particular attention to mitochondrial ROS and inflammatory signaling linked to mitochondrial DNA. The manuscript further evaluates current and emerging interventions, including mitochondria-targeted antioxidants, mitochondrial transfer/transplantation, exercise, dietary approaches, and nanotechnology-enabled delivery systems. For each strategy, we consider the mechanistic rationale, key preclinical findings, and barriers to translation. Across experimental models, many of these approaches confer measurable neuroprotection-often reflected by lower oxidative burden, stabilization of mitochondrial membrane potential, and partial restoration of ATP production. However, clinical findings have been inconsistent, suggesting that efficacy depends strongly on disease stage, patient heterogeneity, and the specific mitochondrial defect being targeted. By integrating mechanistic insights with therapeutic evidence, this review offers a structured perspective on shared and disease-specific features of mitochondrial dysfunction and highlights priorities for advancing mitochondria-centered interventions toward meaningful clinical benefit.