. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A. 2008 May 13;105(19):7070-5. PubMed.

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  1. This paper represents an important extension of our previously published work demonstrating that PINK1 and Parkin interact genetically with components of the mitochondrial morphogenesis machinery. The main findings of Yang et al. are essentially what we reported previously (1), namely that PINK1 acts genetically upstream of the mitochondrial fission promoting component Drp1. But unlike our previous work, which was confined primarily to indirect flight muscle, the current paper demonstrates that this pathway is also conserved in a vertebrate cell line and is relevant to dopaminergic neurons, the cell type that degenerates in Parkinson disease. Thus, two of the three major phenotypes of Drosophila PINK1 and parkin mutants, flight muscle degeneration and dopamine neuron dysfunction, appear to derive from defective mitochondrial fission. The third major phenotype of PINK1 and parkin mutants, a failure to form mature sperm cells, has not yet been shown to derive from an alteration in mitochondrial dynamics, but previous work strongly suggests that a defect in mitochondrial dynamics underlies this phenotype (2). Indeed, unpublished work in the laboratory of Dr. Ming Guo (personal communication) indicates that the germline phenotype of PINK1 mutants is also influenced by alterations in mitochondrial dynamics factors in a fashion that is consistent with what has been reported by our group and by Yang et al.

    In addition to advancing our previous finding that Parkin and PINK1 promote mitochondrial fission, the studies of Yang et al. fill in several gaps that were not thoroughly examined in our work, and also raise several new questions. For example, we found that overexpression of either Drosophila or human PINK1 resulted in a mild rough eye phenotype. Although we showed that this phenotype could be modified by altering the dosage of mitochondrial fission and fusion-promoting factors, we did not explore the underlying cell biology responsible for the PINK1 overexpression phenotype. Yang et al. show that overexpression of PINK1 in dopaminergic neurons results in mitochondrial clustering, suggesting that the eye phenotypes we reported also derive from an underlying alteration in mitochondrial morphology. However, it is unclear whether these mitochondrial clusters represent aggregates of small mitochondria, or a single mitochondrial entity. Moreover, in contrast to our previous work, Yang et al. were unable to influence the PINK1 overexpression phenotype by altering the dosage of Drp1 or Opa1. Perhaps more surprisingly, Yang et al. show that while Parkin overexpression also leads to the formation of mitochondrial clusters, this phenotype requires PINK1 activity—a genetic argument that Parkin acts upstream of PINK1, in contrast to previous work in Drosophila demonstrating that PINK1 acts upstream of Parkin. There are several plausible explanations for these discordant findings and further work should resolve these matters.

    While the finding that PINK1 and Parkin interact genetically with the mitochondrial morphogenesis machinery represents an advance, some important questions remain unanswered from this work. Clearly, the two most important questions concern the mechanism by which the PINK1/Parkin pathway promotes mitochondrial fission and the effects of decreased mitochondrial fission on tissue integrity. Yang et al. argue that the localization of PINK1 to the inner mitochondrial membrane constrains the possible range of substrates of this factor, but several recent reports indicate that a substantial fraction of PINK1 also localizes to the cytoplasm (3-6). This raises the possibility that the PINK1 substrates may not be mitochondrial proteins. Moreover, Parkin has been reported to localize to both the cytoplasm and mitochondria (7,8), so the Parkin substrates may also reside in either of these compartments. Yang et al. also suggest that the neurodegeneration accompanying mutations in PINK1 may result from defective synaptic function owing to the previously reported role of mitochondrial fission in the proper distribution of mitochondria in neurons. While this is a reasonable model, it is also important to note that alterations in mitochondrial dynamics can potentially influence many features of mitochondrial biology, including the rates of ATP synthesis and reactive oxygen species production and the turnover of mitochondria through autophagy (9). An alteration in any one of these processes could profoundly influence tissue viability. Resolving these questions will be an important challenge for our understanding of Parkinson disease, as well as our general understanding of the cell biological roles of mitochondrial dynamics.

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