PINK1 mutants associated with recessive Parkinson’s disease are defective in inhibiting mitochondrial release of cytochrome c

Mitochondrial Biology and Parkinson's Disease

“…et al 2007). Also, overexpression of wild-type PINK1, but not of PD-associated PINK1 mutants, is able to attenuate cytochrome c release, caspase activation, and apoptosis induced by parkinsonian neurotoxins or hydrogen peroxide in cultured cells (Petit et al 2005;Wang et al 2007). Similarly, Parkin was shown to prevent ceramide-induced cytochrome c release, caspase activation, and apoptotic cell death in vitro (Darios et al 2003), an effect that was abolished by PD-causing Parkin mutations (Darios et al 2003).…”

The mitochondrial kinase PINK1, stress response and Parkinson’s disease

“…The loss of functional PINK1 was found to result in increased reactive oxygen species (ROS) levels, enhanced lipid peroxidation, altered glutathione metabolism, enhanced MnSOD levels, impaired glucose import, a decrease of complex I respiration, ATP production, mitochondrial membrane potential and cristae length, a deficit in mtDNA synthesis and levels, an overload of calcium, uncontrolled cytochrome C release, elevated caspase-3 activity and GSK3beta activity (Wang et al , 2007Yang et al 2006;Hoepken et al 2007;Anichtchik et al 2008;Gautier et al 2008;Piccoli et al 2008;WoodKaczmar et al 2008;Gandhi et al 2009;Grünewald et al 2009;Gegg et al 2009;Gispert et al 2009;Marongiu et al 2009). Efficient rescue of this pathology was observed with drugs such as the mitochondrial permeability transition pore blocker cyclosporin A, the mitochondrial calcium influx blocker ruthenium red and the GSK3beta inhibitor LiCl (Anichtchik et al 2008;Marongiu et al 2009).…”

Expression of Pink1 with α-synuclein in the dopaminergic neurons of Drosophila leads to increases in both lifespan and healthspan

“…Mutations in PINK1, and in the Drosophila homologue Pink1, show substantial mitochondrial defects in sensitive tissues, with the inability to inhibit cytochrome c release under stress conditions (Clark et al, 2006;Park et al, 2006;Yang et al, 2006;Exner et al, 2007;Wang et al, 2007). As a protective protein, PINK1 may confer protection of the mitochondria through several mechanisms (Deas et al, 2009), including an interaction with molecular chaperones to regulate oxidative stress responses, activation of the parkin E3 ubiquitin ligase to result in the tagging of toxic proteins, such as α-synuclein, for degradation, or through the initiation of fission events to remove dysfunctional mitochondria via mitophagy.…”