Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W.
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.
Nat Cell Biol. 2010 Feb;12(2):119-31.
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The authors did a marvelous job in providing biochemical and cell biological evidence linking the Pink1/parkin pathway to mitochondrial autophagy. This adds significant new insights into the mechanisms by which the Pink1/parkin pathway regulates mitochondrial morphology and function. What remains to be determined, though, is the in vivo relevance of the findings to dopaminergic neuron maintenance and survival. This is particularly important given recent studies in Drosophila that argue against a role of autophagy in Pink1/parkin pathogenesis (Tain et al., 2009).
We thank Dr. Zhu for citing our work (Iijima-Ando et al., 2009) in his comment. In our Aβ42 fly brain neurons, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. At this stage, organization of microtubules and distribution of synaptic vesicle markers were not significantly altered, suggesting that mitochondrial mislocalization occurs without global axonal transport defects.
By knocking down milton, an adaptor protein that links mitochondria and kinesin, we showed that reduction in mitochondria transport exacerbated Aβ42-induced behavioral defects. Furthermore, milton knockdown by itself caused neuronal dysfunction at a later stage. Our results indicate that Aβ42-induced mitochondrial mislocalization contributes to Aβ42-induced neuronal dysfunction in vivo.
For mitochondrial effects in AD please see our Pharmacogenomics Journal article published in 2009. localizing a variable polyT mutation in the translocase of the outer mitochondrial membrane as a diagnostic predictor of risk for AD.
We thank all the commentators on our paper, "Expression of beta amyloid induced age-dependent presynaptic and axonal changes in Drosophila."
Our examination, through genetic manipulation, of the role of critical mitochondria fission and fusion genes in the mitochondrial abnormalities induced by Aβ expression will be finished soon.