Mitochondrial dysfunction in Parkinson's disease: pathogenesis and neuroprotection

Abstract

Mitochondria are vitally important organelles involved in an array of functions. The most notable is their prominent role in energy metabolism, where they generate over 90% of our cellular energy in the form of ATP through oxidative phosphorylation. Mitochondria are involved in various other processes including the regulation of calcium homeostasis and stress response. Mitochondrial complex I impairment and subsequent oxidative stress have been identified as modulators of cell death in experimental models of Parkinson's disease (PD). Identification of specific genes which are involved in the rare familial forms of PD has further augmented the understanding and elevated the role mitochondrial dysfunction is thought to have in disease pathogenesis. This paper provides a review of the role mitochondria may play in idiopathic PD through the study of experimental models and how genetic mutations influence mitochondrial activity. Recent attempts at providing neuroprotection by targeting mitochondria are described and their progress assessed.

Figure 1

Genetic mutation of α-synuclein and subsequent protein and biochemical alterations. Modifications to the α-synuclein gene cause dysfunction of its protein product. Proteasomal activity becomes impaired, leading to an increased tendency for the protein to aggregate. Mutated α-synuclein protein also localises at the inner mitochondrial membrane, causing complex I dysfunction. ATP production is subsequently reduced, as is the transmembrane potential of the organelle. Increased levels of ROS result, and with mtDNA being particularly susceptible to ROS damage, further cell stress occurs. The acidic cytosolic environment created by ROS and metabolic impairment results in the activation of cell death mediators, such as cytochrome c. Apoptotic pathways are initiated and cell death subsequently occurs.

Figure 2

The physiological association of parkin and PINK1 proteins in mitophagy. (1) Genetic mutations or the introduction of toxins lead to various impairments, including depletion of ATP production at the electron transfer chain. A buildup of ROS leads to a more acidic environment within the mitochondrion, as well as inducing a decrease in the mitochondrial transmembrane potential after the opening of permeability transition pores. This is the signal for mitophagy to occur. (2) The process is induced through the interaction of cytosolic parkin with mitochondria-associated PINK1. PINK1 acts as the biochemical signal for parkin to identify damaged mitochondria. (3) Parkin then mediates the lysosomal degradation of the dysfunctional organelle.