Mitochondria: A Common Target for Genetic Mutations and Environmental Toxicants in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a devastating neurological movement disorder. Since its first discovery 200 years ago, genetic and environmental factors have been identified to play a role in PD development and progression. Although genetic studies have been the predominant driving force in PD research over the last few decades, currently only a small fraction of PD cases can be directly linked to monogenic mutations. The remaining cases have been attributed to other risk associated genes, environmental exposures and gene-environment interactions, making PD a multifactorial disorder with a complex etiology. However, enormous efforts from global research have yielded significant insights into pathogenic mechanisms and potential therapeutic targets for PD. This review will highlight mitochondrial dysfunction as a common pathway involved in both genetic mutations and environmental toxicants linked to PD.

Keywords: Parkinson’s disease; environmental toxins; gene–environment interaction; mitochondrial dynamics; mitochondrial dysfunction; neurodegeneration; neurotoxicity.

FIGURE 1

Common pathogenic mechanisms in Parkinson’s disease. (A) Mitochondrial dysfunction, a common pathogenic mechanism induced by many of the environmental toxicants and genetic mutations linked to PD, results in a cascade of interconnected cellular dysfunction. (B) Neuroinflammation, facilitated by microglia and to a lesser extent astrocytes, which release neurotoxic factors such as cytokines, interleukins and reactive oxygen species, leading to non-cell autonomous neurotoxicity. (C) Increased mitochondrial fission and fragmentation, which can initiate apoptotic cell death by inducing cytochrome C release. (D) Because autophagy and ubiquitin-proteasome system (UPS) are ATP-dependent processes, ATP reduction would reduces autophagic clearance of damaged proteins and organelles. This process is also sensitive to reactive oxygen species (ROS). (E) Generation of ROS, which has the capacity to promote the formation of toxic oligomers and protein aggregates (F), impair ubiquitin proteasomal system function (G), and induce DNA damage (both nuclear and mitochondrial DNA). (H) Nuclear DNA encodes numerous mitochondrial proteins. DNA damage results in altered nuclear function, genomic instabilities, and mitochondrial dysfunction. (I) Dysregulated cellular Ca²⁺ is influenced by mitochondrial dysfunction, because mitochondria help to regulate intracellular Ca²⁺ levels. When damaged, mitochondria release more Ca²⁺ into the cytosol, thereby increasing cellular excitotoxicity. Over-activation of the excitatory receptors also results in excitotoxicity due to Ca²⁺ influx which then produces downstream defects such as Ca²⁺-induced mitochondrial depolarization. As illustrated, all these mechanisms cross-talk and culminate in neurodegenerative processes in PD.

FIGURE 2

Interactions between gene products linked to PD. As discussed in the text, both genetic mutations and neurotoxicants linked to PD impair mitochondrial function, whether directly or indirectly by interacting with each other. For the autosomal recessive gene products, PINK1 is accumulated at outer mitochondrial membrane (OMM) of damaged mitochondria, where it recruits Parkin which ubiquitinates proteins and target them for degradation. Together, PINK1 and Parkin play an important role in maintaining mitochondrial quality through mitophagy. As an antioxidant protein, DJ-1 is translocated to dysfunctional mitochondria when ROS is generated. DJ-1 also aids PINK1 and Parkin in removing damaged mitochondria. Additionally, FBX07 is involved in the recruitment of Parkin to damaged mitochondria and subsequent mitophagy. ATP13A2 is localized in lysosomes and is important for protein degradation. For the autosomal dominant gene products, accumulation of misfolded and aggregated α-synuclein can be induced by a variety of neurotoxicants and genetic mutations. Toxic α-synuclein can impair mitochondrial function, generate ROS and block autophagy/lysosomal function. Mutation in LRRK2 results in gain of toxic kinase function which impairs mitochondrial and autophagic function as well as promotes α-synuclein aggregation. VPS35 mutations increase binding to Drp1 resulting in mitochondrial fragmentation. Of note, mitochondrial fragmentation is a common observation induced by genes and toxicants linked to PD. CHCHD2 is rather unique because it is both a mitochondrial protein and transcription factor. Its mutation impairs complex IV function and expression of a complex IV subunit. Mutations in GBA, a lysosomal protein, impairs protein degradation and mitochondrial function. Although not shown for simplicity, neurotoxicants such as Mn also interact with these proteins (such as α-synuclein) to induce neurotoxicity. Together, there are extensive interactions between these proteins and neurotoxicants leading to neurodegeneration.