Mitochondrial dysfunction. Mitochondria play a crucial role in intracellular energy production, maintenance of Ca2+ homeostasis and apoptosis. Several lines of evidence suggest that mitochondrial dysfunction contributes to ALS. Firstly, altered mitochondrial morphology is found in skeletal muscle and spinal cord motor neurons of ALS patients (Xxxxxx et al., 2007; Xxxxxx and Xxxxx, 2007). Secondly, mitochondrial abnormalities are seen in several transgenic mouse models of ALS including those caused by overexpression of mutant SOD1 and TDP-43 (Xxxx et al., 1995; Xxxx and Xx, 1998; Xx et al., 2010). Thirdly, mutations in the mitochondrial DNA of SALS patients have been shown to lead to a decrease in complex IV proteins in the electron transport chain (Xxxxxxxxx et al., 1999; Xxxxxxxxx et al., 2000). Also, transfer of mitochondrial DNA from ALS patients into human neuroblastoma cells, depleted of their mitochondrial DNA showed functional changes in the electron transport chain, an increase in free radical scavenging enzymes, altered mitochondrial ultrastructure and disturbances of Ca2+ homeostasis (Xxxxxxxx et al., 1998; Xxxxxxxxxxx et al., 2010). Fourthly, mutant SOD1 has been shown to directly damage mitochondria (Xxxxxxx et al., 2002; Xxxxxxx et al., 2006; Xxxxxxxxx et al., 2010). SOD1 is a cytosolic protein and only small proportions are normally found in mitochondria (Xxxxxxxxx et al., 2009). SOD1 is mainly localised in the intermembrane space and only small amounts can be found on the cytoplasmic face of the outer mitochondrial membrane and in the mitochondrial matrix (Xxx et al., 2004; Xxxxxxxxxxxx et al., 2005) where it protects mitochondria from oxidative damage (X'Xxxxx et al., 2004; Xxxxxxxx et al., 2006). Mutant SOD1 aggregates in the mitochondrial matrix of spinal cord neurons but not in other brain cells indicating a direct relevance for disease progression (Xxxxxxxxx et al., 2004; Xxxxx Xxxxx et al., 2008). Aggregated mutant SOD1 directly disturbs mitochondrial function by perturbing enzyme activity of the electron transport chain in early disease stages and disrupting the association of cytochrome c with the outer mitochondrial membrane thereby increasing radical oxygen species (ROS) production, enhancing local excitotoxicity and oxidative damage (Xxxxxx et al., 1999; Xxxxxxxxxx et al., 2005). Additionally mutant SOD1 has been shown to bind directly to the voltage-dependent anion channel 1 (VDAC1) protein that is located in the outer mitochondrial membrane and regulates ...
Mitochondrial dysfunction. Substantial evidence from genetic and toxicological studies suggests that mitochondrial dysfunction is critical to PD pathogenesis. Several proteins implicated in familial forms of PD, including PINK1, DJ-1, Xxxxxx, and HtrA2/Omi, directly or indirectly regulate mitochondrial function (refer to page 16 – 20 for details). Neurotoxins rotenone and MPP+ that induce parkinsonism in animal models also specifically inhibit complex I of mitochondrial electron transport chain and cause mitochondrial dysfunction (refer to page 10-12 for details). The discovery that MPTP, an inhibitor of complex I, causes Parkinsonism in human beings strongly support the hypothesis that mitochondrial dysfunction plays a causal role in PD (187). The toxic effects of MPTP have been repeated in non-human primates and mice, supporting the important role of complex I inhibition in PD pathogenesis. Further evidence comes from other toxicological models using rotenone, another potent inhibitor of complex I. Rats administrated with rotenone develop parkinsonism including presence of α-synuclein positive inclusions. Whether the effects of rotenone are mediated through inhibition of complex I has been tested using a model in which rotenone-insensitive complex I subunit NDI1 was over-expressed unilaterally via viral transduction. Overexpression of NDI1 protects against rotenone induced dopaminergic degeneration, suggesting that rotenone acts through inhibiting complex I (220). Contradictory to this finding, complex I activity seems to be dispensible for rotenone-induced toxicity in mice. Knock out mice lacking NADH ubiquinone oxireductase iron sulfur protein 4 (Ndufs4) gene, which is required for the assembly of complex I, does not affect the susceptibility of dopamine neurons to rotenone induced cell death (61). But the Ndufs4 knockout mice have normal ATP level and oxygen consumption, implying the complex I might be dispensable for aerobic metabolism. However, complex I activity decreases gradually over decades in the pathogenesis of PD, which is different from the sudden complete depletion of complex I in this animal model. Mitochondrial complex I defect has been reported in sporadic PD patients. The SNpc seems to be affected the most, but complex I activity in other brain regions or other tissues is also lower in PD patients compared to normal individuals (124,274,294). The cause of the reduction in complex I activity is unknown but several components of complex I have been shown to be mor...
