Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson's Disease

Abstract

Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations-accounting for ~10% of PD cases-that affect mitochondrial function and are associated with early- or late-onset PD. Early-onset forms typically involve genes encoding proteins essential for mitochondrial quality control, including mitophagy and structural maintenance, while late-onset mutations impair mitochondrial dynamics, bioenergetics, and trafficking. Atypical juvenile genetic syndromes also exhibit mitochondrial abnormalities. In idiopathic PD, environmental neurotoxins such as pesticides and MPTP act as mitochondrial inhibitors, disrupting complex I activity and increasing reactive oxygen species. These converging pathways underscore mitochondria as a central node in PD pathology. This review explores the overlapping and distinct mitochondrial mechanisms in genetic and non-genetic PD, emphasizing their role in neuronal vulnerability. Targeting mitochondrial dysfunction finally offers a promising therapeutic avenue to slow or modify disease progression by intervening at a key point of neurodegenerative convergence.

Keywords: Parkinson’s disease; genetic PD; mitochondrial dysfunction; neurotoxins; oxidative stress.

Figure 1

Mechanisms responsible for mitochondrial dysfunction.

Figure 2

Processes that regulate mitochondrial turnover, such as biogenesis, fusion, fission, mitophagy, and autophagy.

Figure 3

Mitochondrial processes in genetic, non-genetic, and toxic forms of Parkinson’s disease (PD). The gene mutations associated with early- and late-onset PD significantly impair mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and bioenergetics (left panel). Environmental toxins such as MPTP, rotenone, and paraquat inhibit mitochondrial complex I activity (right panel). In genetic- as well as toxin-induced PD, the resulting accumulation of reactive oxygen species (ROS) leads to oxidative stress and ultimately contributes to dopaminergic neuron degeneration.