Letter | Published:

Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin

Naturevolume 441pages11571161 (2006) | Download Citation



Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration1,2. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 (PINK1 )3, a novel AR-JP-linked gene4. Here, we show that PINK1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl-2 demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of PINK1 mutants. Notably, we also found that PINK1 mutants share marked phenotypic similarities with parkin mutants. Transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Shen, J. & Cookson, M. R. Mitochondria and dopamine: new insights into recessive parkinsonism. Neuron 43, 301–304 (2004)

  2. 2

    Moore, D. J., West, A. B., Dawson, V. L. & Dawson, T. M. Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. 28, 57–87 (2005)

  3. 3

    Unoki, M. & Nakamura, Y. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 20, 4457–4465 (2001)

  4. 4

    Valente, E. M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004)

  5. 5

    Vander Heiden, M. G., Chandel, N. S., Williamson, E. K., Schumacker, P. T. & Thompson, C. B. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91, 627–637 (1997)

  6. 6

    Vander Heiden, M. G. & Thompson, C. B. Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? Nature Cell Biol. 1, E209–E216 (1999)

  7. 7

    Quinn, L. et al. Buffy, a Drosophila Bcl-2 protein, has anti-apoptotic and cell cycle inhibitory functions. EMBO J. 22, 3568–3579 (2003)

  8. 8

    Cha, G. H. et al. Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc. Natl Acad. Sci. USA 102, 10345–10350 (2005)

  9. 9

    Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA 100, 4078–4083 (2003)

  10. 10

    Whitworth, A. J. et al. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc. Natl Acad. Sci. USA 102, 8024–8029 (2005)

  11. 11

    Pesah, Y. et al. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131, 2183–2194 (2004)

  12. 12

    Adachi-Yamada, T., Fujimura-Kamada, K., Nishida, Y. & Matsumoto, K. Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature 400, 166–169 (1999)

  13. 13

    Glise, B., Bourbon, H. & Noselli, S. hemipterous encodes a novel Drosophila MAP kinase kinase, required for epithelial cell sheet movement. Cell 83, 451–461 (1995)

  14. 14

    Verstreken, P. et al. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47, 365–378 (2005)

  15. 15

    Friggi-Grelin, F. et al. Targeted gene expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase. J. Neurobiol. 54, 618–627 (2003)

  16. 16

    Lee, S. B., Park, J., Jung, J. U. & Chung, J. Nef induces apoptosis by activating JNK signaling pathway and inhibits NF-κB-dependent immune responses in Drosophila. J. Cell Sci. 118, 1851–1859 (2005)

  17. 17

    Kim, S., Jee, K., Kim, D., Koh, H. & Chung, J. Cyclic AMP inhibits Akt activity by blocking the membrane localization of PDK1. J. Biol. Chem. 276, 12864–12870 (2001)

  18. 18

    Schwarze, S. R., Weindruch, R. & Aiken, J. M. Oxidative stress and aging reduce COX I RNA and cytochrome oxidase activity in Drosophila. Free Radic. Biol. Med. 25, 740–747 (1998)

Download references


We would like to thank H. Richardson, H. J. Bellen, A. Pilling, W. Saxton, T. Adachi-Yamada, E. N. Olson, S. Birman, S. Noselli, E. J. Rulifson and G. M. Rubin for fly stocks. We appreciate B. Graham for helping us to get the effective anti-TH antibodies. We also thank the Korea Basic Science Institute for the use of SEM and TEM electron microscopes. We also thank members of the Chung laboratory for discussions. J.C. is grateful to J. Blenis for his encouragement.

Author information

Author notes

  1. Jeehye Park and Sung Bae Lee: *These authors contributed equally to this work


  1. National Creative Research Initiatives Center for Cell Growth Regulation

    • Jeehye Park
    • , Sung Bae Lee
    • , Sungkyu Lee
    • , Yongsung Kim
    • , Saera Song
    • , Sunhong Kim
    •  & Jongkyeong Chung
  2. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong-Gu, Taejon, 305-701, Korea

    • Jeehye Park
    • , Sung Bae Lee
    • , Sungkyu Lee
    • , Yongsung Kim
    • , Saera Song
    • , Sunhong Kim
    • , Jaeseob Kim
    •  & Jongkyeong Chung
  3. GenExel, Inc., 373-1 Kusong-Dong, Yusong-Gu, Taejon, 305-701, Korea

    • Eunkyung Bae
    •  & Jaeseob Kim
  4. Department of Internal Medicine

    • Minho Shong
  5. Department of Pathology, Chungnam National University School of Medicine, 640 Daesa-Dong, Chung-Gu, Taejon, 301-721, Korea

    • Jin-Man Kim


  1. Search for Jeehye Park in:

  2. Search for Sung Bae Lee in:

  3. Search for Sungkyu Lee in:

  4. Search for Yongsung Kim in:

  5. Search for Saera Song in:

  6. Search for Sunhong Kim in:

  7. Search for Eunkyung Bae in:

  8. Search for Jaeseob Kim in:

  9. Search for Minho Shong in:

  10. Search for Jin-Man Kim in:

  11. Search for Jongkyeong Chung in:

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Jongkyeong Chung.

Supplementary information

  1. Supplementary Notes

    This file contains the Supplementary Methods and Supplementary Figure Legends. (DOC 109 kb)

  2. Supplementary Figures

    This file contains Supplementary Figures 1–8. (PDF 1247 kb)

About this article

Publication history




Issue Date



Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.