The PINK1–Parkin pathway is involved in the regulation of mitochondrial remodeling process

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Abstract

The two Parkinson’s disease (PD) genes, PTEN-induced kinase 1 (PINK1) and parkin, are linked in a common pathway which affects mitochondrial integrity and function. However, it is still not known what this pathway does in the mitochondria. Therefore, we investigated its physiological function in Drosophila. Because Drosophila PINK1 and parkin mutants show changes in mitochondrial morphology in both indirect flight muscles and dopaminergic neurons, we here investigated whether the PINK1–Parkin pathway genetically interacts with the regulators of mitochondrial fusion and fission such as Drp1, which promotes mitochondrial fission, and Opa1 or Marf, which induces mitochondrial fusion. Surprisingly, DrosophilaPINK1 and parkin mutant phenotypes were markedly suppressed by overexpression of Drp1 or downregulation of Opa1 or Marf, indicating that the PINK1–Parkin pathway regulates mitochondrial remodeling process in the direction of promoting mitochondrial fission. Therefore, we strongly suggest that mitochondrial fusion and fission process could be a prominent therapeutic target for the treatment of PD.

Section snippets

Materials and methods

Fly stocks. The generation of park1 mutants, UAS-parkin, PINK1B9 mutants and UAS-PINK1 has been previously described in [16] and [9], respectively. We have generated UAS-drp1 and UAS-drp1K38A (both C-terminally HA-tagged), UAS-opa1 (C-terminally Flag-tagged) and UAS-marf (C-terminally Flag-tagged) transgenic lines, and their expression was confirmed by immunoblot analysis. opa1EP (opa1p{EPgy2}CG8479) [14] and drp12[13] lines were obtained from Dr. A. Mcquibban (University of Toronto) and Dr. H.

Results and discussion

We and others have previously found that DrosophilaPINK1 and parkin mutants show mitochondrial swelling in the indirect flight muscle [9], [10], [11], so we sought to observe the mitochondrial morphology when both PINK1 and Parkin are overexpressed. Coexpression of PINK1 and Parkin under the hs-GAL4 driver resulted in pupal lethality when raised at 25 °C, but at 18 °C several adult escapees came out and we found smaller mitochondria in the indirect flight muscle compared to the control (Fig. 1A).

Funding

This research was supported by a National Creative Research Initiatives Grant (R16-2001-002-01001-0) from Korean Ministry of Education, Science and Technology/KOSEF.

Conflicts of interest

The authors declare no competing financial interests.

Acknowledgments

We are grateful to Drs. A. Mcquibban, H. J. Bellen, S. Birman, for providing us fly stocks. We also thank Chung’s laboratory members for helpful discussions.

References (23)

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      To do so, we directly manipulated Drp1, a dynamin-related protein that promotes mitochondrial fission (Hoppins et al., 2007). More specifically, we inhibited mitochondrial fission, by inducing a dominant-negative Drp1 (Drp1K38A) transgene (Park et al., 2009), from midlife onward in flies with increased dp62 levels and examined the impact on mitochondrial morphology, mitochondrial function, and compared survivorship to flies with increased dp62 alone. We confirmed that inducing dominant-negative Drp1 (Drp1K38A) from midlife onward in flies with increased dp62 levels (Figure S7A) prevented an increase in mitochondrial fission (Figures 6A and 6B; quantification in Figure 6C).

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