Figure 3.

Role of the major PD-associated genes in mitochondrial dysfunction. Many genes associated with Parkinson disease (PD) implicate a role for mitochondria in the pathogenesis of the disease. The serine protease HTRA2–OMI is synthesised as an inactive precursor containing a mitochondrial-targeting sequence (MTS). In response to the activation of the MEKK3–p38 stress-kinase-signalling pathway, HTRA2/OMI is phosphorylated by p38 in a PINK1-dependent manner and imported into the intermembrane space (IMS), where it has been reported to bind to the Bcl-2-family-related protein Hax-1 (Ref. 117). Despite the fact that this interaction is controversial (Ref. 118), it has been suggested to promote the proteolytic processing of HTRA2/OMI by the mitochondrial protease PARL. Active HTRA2/OMI is thought to be involved in the degradation of misfolded proteins present in the IMS (Ref. 119) and to prevent the oligomerisation of the activated form of BAX on the outer membrane (OM), thus avoiding apoptosis (Ref. 117). Under oxidative stress conditions, PINK1 also interacts with the mitochondrial molecular chaperone TRAP1. Once phosphorylated, TRAP1 inhibits oxidative-stress-induced cytochrome c (Cyt C) release, prevents misfolding and promotes the correct assembly of mitochondrial proteins. DJ-1 is a cytosolic oxidative-stress-regulated chaperone, which redistributes from the cytosol to the mitochondria upon oxidation of specific cysteine residues. In the cytoplasm, DJ-1 prevents the aggregation and toxicity of α-synuclein (α-syn); in mitochondria, it has been suggested to protect respiratory complex I (cI) from oxidative-stress-mediated inactivation (Ref. 23). Another protein involved in the mitochondrial stress response is Parkin, a cytosolic E3-ubiquitin ligase, which is selectively recruited to uncoupled or dysfunctional mitochondria, targeting them for autophagy (Ref. 28). A model is illustrated whereby PINK1, acting upstream of Parkin, might regulate mitochondrial function by sensing mitochondrial damage, recruiting Parkin and inducing mitophagy. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine-5^′-triphosphate; cII, complex II; cIII, complex III; cIV, complex IV, cV, complex V; HAX-1, HCLS1-associated protein X-1; HTRA2, high-temperature requirement A2; IM, mitochondrial inner membrane; MEKK3, mitogen-activated protein kinase kinase kinase 3; PINK1, PTEN-induced putative kinase 1; PD, Parkinson disease; PDZ domain, post-synaptic density protein (PSD95), Drosophila discs large tumour suppressor (DlgA) and zonula occludens-1 protein (zo-1) domain; TRAP1, TNF-receptor associated protein; Δψ_m, mitochondrial membrane potential.