Keeping mitochondria trim and fit is good for your health, yet in Parkinson disease (PD) these organelles are all but healthy. That may be because they swell and fail to divide as normal. In the April 28 PNAS online, researchers led by Bingwei Lu at Stanford University, Palo Alto, California, report that Pink1, a key player in the pathology of some inherited forms of PD, is crucial for mitochondrial fission. The researchers also report that promoting fission of the organelles suppresses pathology in Pink1 mutant flies. “Our findings link mitochondrial fission/fusion to PD pathogenesis and suggest ways to understand and treat PD and related disorders,” write the authors.

Mitochondria, the power plants of the cell, can grow and divide, but they can also fuse together. Scientists are only just beginning to understand the dynamics behind this fission and fusion, and whether it has any bearing on disease. This latest work comes on the heels of a recent paper, which also reported that Pink1 regulates mitochondrial fission/fusion in fruit flies. Leo Pallanck’s lab at the University of Washington, Seattle, had shown that flightless Pink1 and parkin mutants could be rescued by promoting mitochondrial fission (see ARF related news story).

Lu and colleagues used a similar approach to address the question of mitochondrial pathology in fly models of PD. First author Yufeng Yang and colleagues report that either stimulating mitochondrial fission (by overexpressing the fission protein Drp1) or preventing fusion (by removing a copy of the fusion protein OpaI-like) corrected the bad wing posture found in Pink1 mutant flies. The same strategies also rescued mitochondrial morphology (in Pink1 mutants the organelles are enlarged with disorganized membranes) and the organization of the indirect flight muscle fibers, which are thin and atrophied in mutant flies.

Yang and colleagues also addressed whether Pink1’s role in regulating mitochondria has any bearing for neurons, which is more relevant to PD. In the fly brain, dopaminergic neurons are found in the dorsolateral protocerebral posterior clusters. In Pink1 mutant flies, mitochondria aggregate in those neurons and/or form tubular structures that are not normal. But when Yang and colleagues overexpressed the pro-fission protein Drp1, they found no aggregates and the mitochondria were normally distributed. “Our results demonstrate that Pink1 regulates mitochondrial morphogenesis and function through the fission/fusion pathway in indirect flight muscle and dopaminergic neurons,” write the authors.

The results build on Pallanck and colleagues’ findings. Together the two papers support the notion that Pink1 and parkin mutations cause mitochondrial pathology in humans, as well. In fact, other mutations that impact the mitochondrial fission/fusion apparatus have been linked to Charcot-Marie-Tooth disease (Kijima et al., 2005), blindness (see Alexander et al., 2000), and abnormal and fatal brain development in humans (see Waterham et al., 2007).—Tom Fagan


  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.


    . The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43. PubMed.

    . The Drosophila parkin homologue is required for normal mitochondrial dynamics during spermiogenesis. Dev Biol. 2007 Mar 1;303(1):108-20. PubMed.

    . Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1716-21. PubMed.

    . Characterization of PINK1 processing, stability, and subcellular localization. J Neurochem. 2008 Jul;106(1):464-74. PubMed.

    . Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci Lett. 2008 Jan 3;430(1):13-7. PubMed.

    . Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1. Hum Mol Genet. 2008 Feb 15;17(4):602-16. PubMed.

    . Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet. 2003 Mar 1;12(5):517-26. PubMed.

    . Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet. 2006 Mar 15;15(6):883-95. PubMed.

    . Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death Differ. 2008 Jul;15(7):1147-52. PubMed.

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News Citations

  1. Pink Fission—Serving Up a Rationale for Parkinson Disease?

Paper Citations

  1. . Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet. 2005 Jan;116(1-2):23-7. PubMed.
  2. . OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000 Oct;26(2):211-5. PubMed.
  3. . A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007 Apr 26;356(17):1736-41. PubMed.

External Citations

  1. Pink1

Further Reading

Primary Papers

  1. . 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.