Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

INTRODUCTION
Mitochondrial dysfunction
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Many data support now a role for aberrant mitochondrial form and function in
the pathogenesis of PD (Schapira 2008). Mitochondria are essential for the generation
of cellular energy through oxidative phosphorylation. They are also the major cellular
source of free radicals and are implicated in the regulation and initiation of cell death
pathways and in calcium homeostasis. Mitochondria dysfunction can lead to insufficient
ATP production hence impairing all ATP-dependent cellular processes and generate and
accumulate ROS, rendering then cells more vulnerable to oxidative stress and other
interconnected processes, including excitotoxicity. Originally, MPTP toxicity and
reduction of complex I activity in the SNpc of PD patients provided evidence for the
participation of mitochondrial pathways in PD (Schapira et al. 1992, Mann et al. 1994).
Moreover, demonstration of the involvement of PD-associated genes products in
mitochondrial function reinforced the connection between PD and mitochondrial
biology (Dodson and Guo 2007). Mutations of these PD-associated genes will likely
disrupt mitochondrial function and affect the cellular response to oxidative stress.
PINK1, a mitochondrial serine-threonine kinase that shares homology with
calmodulin (CaM)-dependent protein kinase I, localizes principally within
mitochondria, in particular at the outer mitochondrial membrane (Zhou et al. 2008)
while others suggested an inner mitochondrial membrane localization (Silvestri et al.
2005, Gandhi et al. 2006) or a cytoplasmic pool (Weihofen et al. 2007, Haque et al.
2008). PINK1 seems to provide protection against oxidative stress (Valente et al. 2004,
Yang et al. 2006). Its overexpression defends cell from mitochondrially-induced
apoptosis caused by staurosporine, and from mitochondrial depolarization and apoptosis
generated by the proteasomal inhibitor MG132 (Wood-Kaczmar et al. 2008). PINK1 is
thought to interact with HTRA2 (Plun-Favreau et al. 2007), a mitochondrial serine
protease, that is released from the mitochondrial intermembrane space into the cytosol,
where it induces apoptotic cell death in addition to the permeabilization of the
mitochondrial membrane leading to cytochrome c release (Suzuki et al. 2001, Hegde et
al. 2002, Suzuki et al. 2004). Furthermore, recent studies suggest that PINK1 could act