Pink1 and parkin demonstrate multifaceted roles when co-expressed with Foxo

Abstract

Pink1 has been linked to both autosomal recessive and sporadic forms of Parkinson disease. The Pink1 protein is thought to be involved in mitochondrial protection by interacting with parkin to prevent oxidative damage, maintain mitochondrial integrity and regulate mitophagy. Pink1 and parkin have been linked to components of the insulin receptor (INR) pathway, including PTEN, Akt and Foxo, but their effects in the INR pathway have been largely overlooked. To further investigate the roles of Pink1/parkin, we have performed co-expression studies to determine the effects Pink1 and parkin on the Foxo-induced phenotype of developmental defects in the Drosophila eye. We examined directed expression of Pink1, parkin, Pink1 or parkin mutants, and Pink1 or parkin interfering RNAs (RNAi) with the overexpression of Foxo in the developing eye of Drosophila. Our findings show that reduction of Pink1 suppresses the effects of Foxo overexpression, where co-overexpression with Pink1 or parkin increases the severity of the phenotype. This suggests that Pink1 and parkin are able to increase the pro-apoptotic effects of Foxo. Contrary to the view that Pink1 and parkin act exclusively as protective proteins in the cell, it is likely that the Pink1/parkin pathway is involved in aspects of cell fate decisions other than degrading toxic proteins and maintaining mitochondrial integrity.

Share and Cite:

M. Todd, A. and E. Staveley, B. (2013) Pink1 and parkin demonstrate multifaceted roles when co-expressed with Foxo. Advances in Parkinson's Disease, 2, 5-10. doi: 10.4236/apd.2013.21002.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Jendrach, M., Gispert, S., Ricciardi, F., Klinkenberg, M., Schemm, R. and Auburger, G. (2009) The mitochondrial kinase Pink1, stress response and Parkinson’s disease. Journal of Bioenergetics Biomembranes, 41, 481-486. doi: 10.1007/s10863-009-9256-0
[2] Valente, E.M., Abou-Sleiman, P.M., Caputo, V., Muqit, M.M., Harvey, K., Gispert, S., et al. (2004) Hereditary early-onset Parkinson’s disease caused by mutations in Pink1. Science, 304, 1158-1160. doi: 10.1126/science.1096284
[3] Valente, E.M., Salvi, S., Ialongo, T., Marongiu, R., Elia, A.E., Caputo, V., et al. (2004) Pink1 mutations are associated with sporadic early-onset parkinsonism. Annals of Neurology, 56, 336-341. doi: 10.1002/ana.20256
[4] Clark, I.E., Dodson, M.W., Jiang, C., Cao, J.H., Huh, J.R., Seol, J.H., et al. (2006) Drosophila Pink1 is required for mitochondrial function and interacts genetically with parkin. Nature, 441, 1162-1166. doi: 10.1038/nature04779
[5] Exner, N., Treske, B., Paquet, D., Holmstrom, K., Schiesling, C., Gispert, S., et al. (2007) Loss-of-function of human Pink1 results in mitochondrial pathology and can be rescued by parkin. The Journal of Neuroscience, 27, 12413-12418.
[6] Park, J., Lee, S.B., Lee, S., Kim, Y., Song, S., Kim, S., et al. (2006) Mitochondrial dysfunction in Drosophila Pink1 mutants is complemented by parkin. Nature, 441, 1157-1161.
[7] Yang, Y., Gehrke, S., Imai, Y., Huang, Z., Ouyang, Y., Wang, J.W., et al. (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proceedings of the National Academy of Sciences of United States of America, 103, 10793-10798. doi: 10.1073/pnas.0602493103
[8] Hoepken, H.H., Gispert, S., Morales, B., Wingerter, O., Del Turco, D., Mulsch, A., et al. (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiology of Disease, 25, 401-411. doi: 10.1016/j.nbd.2006.10.007
[9] Chu, C.T. (2010) A pivotal role for Pink1 and autophagy in mitochondrial quality control: Implications for Parkinson disease. Human Molecular Genetics, 19, R28-37. doi: 10.1093/hmg/ddq143
[10] Yang, Y., Ouyang, Y., Yang, L., Beal, M.F., McQuibban, A., Vogel, H., et al. (2008) Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proceedings of the National Academy of Sciences of United States of America, 105, 7070-7075. doi: 10.1073/pnas.0711845105
[11] Poole, A.C., Thomas, R.E., Andrews, L.A., McBride, H.M., Whitworth, A.J. and Pallanck, L.J. (2008) The Pink1/Parkin pathway regulates mitochondrial morphology. Proceedings of the National Academy of Sciences of United States of America, 105, 1638-1643. doi: 10.1073/pnas.0709336105
[12] Gegg, M.E., Cooper, J.M., Chau, K.Y., Rojo, M., Schapira, A.H. and Taanman, J.W. (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a Pink1/parkindependent manner upon induction of mitophagy. Human Molecular Genetics, 19, 4861-4870. doi: 10.1093/hmg/ddq419
[13] Vives-Bauza, C., Zhou, C., Huang, Y., Cui, M., de Vries, R.L., Kim, J., et al. (2010) Pink1-dependent recruitment of Parkin to mitochondria in mitophagy. Proceedings of the National Academy of Sciences of United States of America, 107, 378-383. doi: 10.1073/pnas.0911187107
[14] Geisler, S., Holmstrom, K.M., Skujat, D., Fiesel, F.C., Rothfuss, O.C., Kahle, P.J., et al. (2010) Pink1/Parkinmediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biology, 12, 119-131. doi: 10.1038/ncb2012
[15] Ziviani, E., Tao, R.N. and Whitworth, A.J. (2010) Drosophila parkin requires Pink1 for mitochondrial translocation and ubiquitinates mitofusin. Proceedings of the National Academy of Sciences of United States of America, 107, 5018-5023. doi: 10.1073/pnas.0913485107
[16] Dagda, R.K., Cherra, S.J., 3rd, Kulich, S.M., Tandon, A., Park, D. and Chu, C.T. (2009) Loss of Pink1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. The Journal of Biological Chemistry 284, 13843-13855. doi: 10.1074/jbc.M808515200
[17] Lutz, A.K., Exner, N., Fett, M.E., Schlehe, J.S., Kloos, K., Lammermann, K., et al. (2009) Loss of parkin or Pink1 function increases Drp1-dependent mitochondrial fragmentation. The Journal of Biological Chemistry 284, 22938-22951. doi: 10.1074/jbc.M109.035774
[18] Unoki, M. and Nakamura, Y. (2001) Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene, 20, 4457-4465. doi: 10.1038/sj.onc.1204608
[19] Kim, R.H., Peters, M., Jang, Y., Shi, W., Pintilie, M., Fletcher, G.C., et al. (2005) DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell, 7, 263-273. doi: 10.1016/j.ccr.2005.02.010
[20] Kim, Y.C., Kitaura, H., Taira, T., Iguchi-Ariga, S.M. and Ariga, H. (2009) Oxidation of DJ-1-dependent cell transformation through direct binding of DJ-1 to PTEN. International Journal of Oncology, 35, 1331-1341.
[21] Fallon, L., Belanger, C.M., Corera, A.T., Kontogiannea, M., Regan-Klapisz, E., Moreau, F., et al. (2006) A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nature Cell Biology, 8, 834-842. doi: 10.1038/ncb1441
[22] Aleyasin, H., Rousseaux, M.W., Marcogliese, P.C., Hewitt, S.J., Irrcher, I., Joselin, A.P., et al. (2010) DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway. Proceedings of the National Academy of Sciences of United States of America, 107, 3186-3191. doi: 10.1073/pnas.0914876107
[23] Yang, Y., Gehrke, S., Haque, M.E., Imai, Y., Kosek, J., Yang, L., et al. (2005) Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proceedings of the National Academy of Sciences of United States of America, 102, 13670-13675. doi: 10.1073/pnas.0504610102
[24] Mei, Y., Zhang, Y., Yamamoto, K., Xie, W., Mak, T.W. and You, H. (2009) Foxo3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation. Proceedings of the National Academy of Sciences of United States of America, 106, 5153-5158. doi: 10.1073/pnas.0901104106
[25] Sengupta, A., Molkentin, J.D., Paik, J.H., Depinho, R.A. and Yutzey, K.E. (2011) Foxo transcription factors promote cardiomyocyte survival upon Induction of Oxidative Stress. The Journal of Biological Chemistry 286, 7468-7478. doi: 10.1074/jbc.M110.179242
[26] Koh, H., Kim, H., Kim, M.J., Park, J., Lee, H.J. and Chung, J. (2012) Silent information regulator 2 (Sir2) and forkhead box O (Foxo) complement mitochondrial dysfunction and dopaminergic neuron loss in Drosophila PTEN-induced kinase 1 (Pink1) null mutant. The Journal of Biological Chemistry, 287, 12750-12758. doi: 10.1074/jbc.M111.337907
[27] Greer, E.L. and Brunet, A. (2005) Foxo transcription factors at the interface between longevity and tumor suppression. Oncogene, 24, 7410-7425. doi: 10.1038/sj.onc.1209086
[28] van der Horst, A. and Burgering, B.M. (2007) Stressing the role of Foxo proteins in lifespan and disease. Nature Reviews: Molecular Cell Biology, 8, 440-450. doi: 10.1038/nrm2190
[29] Kanao, T., Venderova, K., Park, D.S., Unterman, T., Lu, B. and Imai, Y. (2010) Activation of Foxo by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Human Molecular Genetics, 19, 3747-3758. doi: 10.1093/hmg/ddq289
[30] Kanao, T., Sawada, T., Davies, S.A., Ichinose, H., Hasegawa, K., Takahashi, R., et al. (2012) The nitric oxidecyclic GMP pathway regulates Foxo and alters dopaminergic neuron survival in Drosophila. PLoS One, 7, e30958. doi: 10.1371/journal.pone.0030958
[31] Kramer, J.M., Davidge, J.T., Lockyer, J.M. and Staveley, B.E. (2003) Expression of Drosophila Foxo regulates growth and can phenocopy starvation. BMC Developmental Biology, 3, 5. doi: 10.1186/1471-213X-3-5
[32] Todd, A.M. and Staveley, B.E. (2008) Pink1 suppresses alpha-synuclein-induced phenotypes in a Drosophila model of Parkinson’s disease. Genome, 51, 1040-1046. doi: 10.1139/G08-085
[33] Haywood, A.F. and Staveley, B.E. (2004) Parkin counteracts symptoms in a Drosophila model of Parkinson’s disease. BMC Neuroscience, 5, 14. doi: 10.1186/1471-2202-5-14
[34] Yang, Y., Nishimura, I., Imai, Y., Takahashi, R. and Lu, B. (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron, 37, 911-924. doi: 10.1016/S0896-6273(03)00143-0
[35] Greene, J.C., Whitworth, A.J., Kuo, I., Andrews, L.A., Feany, M.B. and Pallanck, L.J. (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proceedings of the National Academy of Sciences of United States of America, 100, 4078-4083. doi: 10.1073/pnas.0737556100
[36] Biggs, W.H., 3rd, Meisenhelder, J., Hunter, T., Cavenee, W.K. and Arden, K.C. (1999) Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proceedings of the National Academy of Sciences of United States of America, 96, 7421-7426. doi: 10.1073/pnas.96.13.7421
[37] Wilson, R., Goyal, L., Ditzel, M., Zachariou, A., Baker, D.A., Agapite, J., et al. (2002) The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis. Nature Cell Biology, 4, 445-450. doi: 10.1038/ncb799
[38] Green, D.R. and Kroemer, G. (2004) The pathophysiology of mitochondrial cell death. Science, 305, 626-629.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.