The lysosome is considered a principle cellular reservoir for the safe storage of redox reactive iron. When lysosomal pH is disrupted, iron is released from the lysosome into the cytosol where it can be taken into the mitochondria via the membrane calcium uniporter. Once inside the mitochondria, the presence of elevations in redox reactive iron can result in increases in levels of mitochondrial oxidative stress, reductions in the mitochondrial membrane potential (MMP), and cell death. Lysosomal pH has recently been reported to be compromised in the context of mutations in the ATP13A2 gene resulting in an early onset form of Parkinson's disease (PD) known as Kufer-Rakeb syndrome. The ATP13A2 gene itself encodes a proton-pumping lysosomal ATPase whose loss of activity has been shown to disrupt both cellular iron homeostasis and mitochondrial function. We propose that ATP13A2 deficit results in a redistribution of chelatable iron which in turn predisposes neurons for increases in mitochondrial dysfunction and cell loss. This would constitute a novel function for ATP13A2 which could have important implications for mechanisms underlying the loss of cellular iron homeostasis associated with PD neuropathology.
The PHD2-HIF1? signaling pathway regulates a number of neuroprotective genes including those involved in the maintenance of cellular iron homeostasis; recent unpublished data from our laboratory demonstrates that ATP13A2, a gene whose mutation is associated with Kufer-Rakeb syndrome and encoding a proton-pumping lysosomal ATPase, is a downstream target of this pathway. We hypothesize that neurodegenerative effects associated with disruption of ATP13A2 are due to losses in lysosomal iron storage resulting in release into the cytosol and uptake by the mitochondria. Our goal in this present proposal is to interrogate whether a redistribution of chelatable iron occurs as a consequence of ATP13A2 deficit, the mechanisms underlying this alteration, and whether this in turn predisposes neurons for increases in mitochondrial dysfunction and cell loss.
