Mitochondrial Dysfunction in Parkinson?s Disease: Mechanistic Insights and Emerging Therapeutic Strategies
Author(s): Anastasia V. Poznyak*, Alexander L. Golovyuk, Fu Changgeng, Li Hongzheng, Elizaveta Romanovna Korchagina, Alexander N. Orekhov
Abstract
Mitochondrial dysfunction is a major contributor to multifactorial neurodegenerative disease, Parkinson’s Disease (PD). The molecular links between mitochondrial dysfunction and the causes of PD are summarised here in light of our current knowledge. Using data from genetic and subjective studies, we identify the mitochondrial pathways impacted by α-synuclein aggregation, oxidative stress, dysregulated calcium signalling, and reduced mitophagy. Particular focus is on the link between mitochondria, lysosomes, and the endoplasmic reticulum as well as how these interorganelle interactions contribute to neuronal vulnerability. Evidence gathered suggests a decline in oxidative phosphorylation, an increase in Reactive Oxygen Species (ROS) production, and the activation of programmed cell death pathways as mitochondrial dysfunction contributes to dopaminergic neuron death. Further modifications in the PINK1, Parkin, and other genes related to PD lead to additional alterations in the processes controlling mitochondrial quality, triggering neuroinflammation via the cGAS-STING and NLRP3 inflammasome pathways. Identifying the principal unifying mechanism in the pathophysiology of PD as mitochondrial malfunction provides new therapeutic options. Among the most promising treatments are increased mitophagy, enhanced mitochondrial biogenesis, and reduced oxidative stress especially via gene therapy, PGC-1α activation, and mitochondrial targeted antioxidants.