The multi‐faceted role of mitochondria in the pathology of Parkinson’s disease

Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and regulate reactive oxygen species that cause oxidative cellular stress. Mitochondria have also been shown to regulate protein synthesis within themselves, as well as within the nucleus, and also influence synaptic plasticity. These roles are especially important for neurons, which have higher energy demands and greater susceptibility to stress. Dysfunction of mitochondria has been associated with several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, Glaucoma and Amyotrophic Lateral Sclerosis. The focus of this review is on how and why mitochondrial function is linked to the pathology of Parkinson's disease (PD). Many of the PD‐linked genetic mutations which have been identified result in dysfunctional mitochondria, through a wide‐spread number of mechanisms. In this review, we describe how susceptible neurons are predisposed to be vulnerable to the toxic events that occur during the neurodegenerative process of PD, and how mitochondria are central to these pathways. We also discuss ways in which proteins linked with familial PD control mitochondrial function, both physiologically and pathologically, along with their implications in genome‐wide association studies and risk assessment. Finally, we review potential strategies for disease modification through mitochondrial enhancement. Ultimately, agents capable of both improving and/or restoring mitochondrial function, either alone, or in conjunction with other disease‐modifying agents may halt or slow the progression of neurodegeneration in Parkinson's disease. In Parkinson's disease (PD), mitochondria of dopaminergic neurons in the SNc are more susceptible to cellular stress than other neurons, which contribute to neurodegeneration. Susceptibility to mitochondrial stress is caused by genetic and innate factors which converge to cause mitochondrial dysfunction. This results in the pathology and symptoms of PD. Mitochondrial enhancers that target mitochondrial abnormalities have the potential to restore mitochondrial function, and so alleviate PD pathology, and thus symptoms. Created with BioRender.com figure