Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Mitochondrial Uncoupling Attenuates Age-Dependent Neurodegeneration in C. elegans

  • Cho, Injeong (Department of Biology Education, College of Education, Chosun University) ;
  • Song, Hyun-Ok (Department of Infection Biology, Wonkwang University School of Medicine) ;
  • Cho, Jeong Hoon (Department of Biology Education, College of Education, Chosun University)
  • Received : 2017.08.16
  • Accepted : 2017.09.21
  • Published : 2017.11.30
Download PDF
⟨ Previous Next ⟩

Abstract

The uncoupling protein 4 (ucp-4) gene is involved in age-dependent neurodegeneration in C. elegans. Therefore, we aimed to investigate the mechanism underlying the association between mitochondrial uncoupling and neurodegeneration by examining the effects of uncoupling agents and ucp-4 overexpression in C. elegans. Treatment with either DNP or CCCP improved neuronal defects in wild type during aging. Uncoupling agents also restored neuronal phenotypes of ucp-4 mutants to those exhibited by wild type, while ucp-4 overexpression attenuated the severity of age-dependent neurodegeneration. Neuronal improvements were further associated with reductions in mitochondrial membrane potentials. However, these age-dependent neuroprotective effects were limited in mitophagy-deficient mutant, pink-1, background. These results suggest that membrane uncoupling can attenuate age-dependent neurodegeneration by stimulating mitophagy.

Keywords

References

  1. Allen, G.F., Toth, R., James, J., and Ganley, I.G. (2013). Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep. 14, 1127-1135. https://doi.org/10.1038/embor.2013.168
  2. Ashrafi, G., and Schwarz, T.L. (2013). The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31-42. https://doi.org/10.1038/cdd.2012.81
  3. Berezhnov, A.V., Soutar, M.P., Fedotova, E.I., Frolova, M.S., Plun-Favreau, H., Zinchenko, V.P., and Abramov, A.Y. (2016). Intracellular pH modulates autophagy and mitophagy. J. Biol. Chem. 291, 8701-8708. https://doi.org/10.1074/jbc.M115.691774
  4. Bossy-Wetzel, E., Petrilli, A., and Knott, A.B. (2008). Mutant huntingtin and mitochondrial dysfunction. Trends Neurosci. 31, 609-616. https://doi.org/10.1016/j.tins.2008.09.004
  5. Brenner, S. (1974) The genetics of Caenorhabditis elegans. Genetics 77, 71-94.
  6. Caldeira da Silva, C.C., Cerqueira, F.M., Barbosa, L.F., Medeiros, M.H., and Kowaltowski, A.J. (2008). Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell 7, 552-560. https://doi.org/10.1111/j.1474-9726.2008.00407.x
  7. Chen, C.H., Chen, Y.C., Jiang, H.C., Chen, C.K., and Pan, C.L. (2013). Neuronal aging: learning from C. elegans. J. Mol. Signal. 8, 14. https://doi.org/10.1186/1750-2187-8-14
  8. Cho, I., Hwang, G.J., and Cho, J.H. (2016). Uncoupling protein, UCP-4 may be involved in neuronal defects during aging and resistance to pathogens in Caenorhabditis elegans. Mol. Cells 39, 680-686. https://doi.org/10.14348/molcells.2016.0125
  9. Ehrenberg, B., Montana, V., Wei, M.D., Wuskell, J.P., and Loew, L.M. (1988). Membrane potential can be determined in individual cells from the nernstian distribution of cationic dyes. Biophys. J. 53, 785-794. https://doi.org/10.1016/S0006-3495(88)83158-8
  10. Farkas, D.L., Wei, M.D., Febbroriello, P., Carson, J.H., and Loew, L.M. (1989). Simultaneous imaging of cell and mitochondrial membrane potentials. Biophys. J. 56, 1053-1069. https://doi.org/10.1016/S0006-3495(89)82754-7
  11. Geisler, J.G., Marosi, K., Halpern, J., and Mattson, M.P. (2017). DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya. Alzheimers Dement 13, 582-591. https://doi.org/10.1016/j.jalz.2016.08.001
  12. Georgakopoulos, N.D., Wells, G., and Campanella, M. (2017). The pharmacological regulation of cellular mitophagy. Nat. Chem. Biol. 13, 136-146. https://doi.org/10.1038/nchembio.2287
  13. Grimm, A., and Eckert, A. (2017). Brain aging and neurodegeneration: from a mitochondrial point of view. J. Neurochem.
  14. Itoh, K., Nakamura, K., Iijima, M., and Sesaki, H. (2013). Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 23, 64-71. https://doi.org/10.1016/j.tcb.2012.10.006
  15. Kalogeris, T., Bao, Y., and Korthuis, R.J. (2014). Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox. Biol. 2, 702-714. https://doi.org/10.1016/j.redox.2014.05.006
  16. Kerr, J.S., Adriaanse, B.A., Greig, N.H., Mattson, M.P., Cader, M.Z., Bohr, V.A., and Fang, E.F. (2017.) Mitophagy and Alzheimer's disease: cellular and molecular mechanisms. Trends Neurosci. 40, 151-166. https://doi.org/10.1016/j.tins.2017.01.002
  17. Lazarou, M., Sliter, D.A., Kane, L.A., Sarraf, S.A., Wang, C., Burman, J.L., Sideris, D.P., Fogel, A.I., and Youle, R.J. (2015). The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309-314. https://doi.org/10.1038/nature14893
  18. MacVicar, T.D., and Lane, J.D. (2014). Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation. J. Cell Sci. 127, 2313-2325. https://doi.org/10.1242/jcs.144337
  19. Mello, C., and Fire, A. (1995). DNA transformation. Methods Cell Biol. 48, 451-482.
  20. Moriya, H. (2015). Quantitative nature of overexpression experiments. Mol. Biol. Cell. 26, 3932-3939. https://doi.org/10.1091/mbc.E15-07-0512
  21. Narendra, D., Tanaka, A., Suen, D.F., and Youle, R.J. (2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795-803. https://doi.org/10.1083/jcb.200809125
  22. Narendra, D.P., Jin, S.M., Tanaka, A., Suen, D.F., Gautier, C.A., Shen, J., Cookson, M.R., and Youle, R.J. (2010). PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298. https://doi.org/10.1371/journal.pbio.1000298
  23. Palikaras, K., Lionaki, E., and Tavernarakis, N. (2015). Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525-528. https://doi.org/10.1038/nature14300
  24. Pan, C.L., Peng, C.Y., Chen, C.H., and McIntire, S. (2011). Genetic analysis of age-dependent defects of the Caenorhabditis elegans touch receptor neurons. Proc. Natl. Acad. Sci. USA 108, 9274-9279. https://doi.org/10.1073/pnas.1011711108
  25. Prelich, G. (2012). Gene overexpression: uses, mechanisms, and interpretation. Genetics 190, 841-854. https://doi.org/10.1534/genetics.111.136911
  26. Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W., and Ferri, C.P. (2013). The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9, 63-75.e62. https://doi.org/10.1016/j.jalz.2012.11.007
  27. Rugarli, E.I., and Langer, T. (2012). Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 31, 1336-1349. https://doi.org/10.1038/emboj.2012.38
  28. Tank, E.M., Rodgers, K.E., and Kenyon, C. (2011). Spontaneous agerelated neurite branching in Caenorhabditis elegans. J. Neurosci. 31, 9279-9288. https://doi.org/10.1523/JNEUROSCI.6606-10.2011
  29. Toth, M.L., Melentijevic, I., Shah, L., Bhatia, A., Lu, K., Talwar, A., Naji, H., Ibanez-Ventoso, C., Ghose, P., Jevince, A., et al. (2012). Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. J. Neurosci. 32, 8778-8790. https://doi.org/10.1523/JNEUROSCI.1494-11.2012
  30. Villace, P., Mella, R.M., and Kortazar, D. (2017). Mitochondria in the context of Parkinson's disease. Neural Regen. Res. 12, 214-215. https://doi.org/10.4103/1673-5374.200802
  31. Wu, Y.N., Munhall, A.C., and Johnson, S.W. (2011). Mitochondrial uncoupling agents antagonize rotenone actions in rat substantia nigra dopamine neurons. Brain Res. 1395, 86-93. https://doi.org/10.1016/j.brainres.2011.04.032
  32. Yoneda, T., Benedetti, C., Urano, F., Clark, S.G., Harding, H.P., and Ron, D. (2004). Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J. Cell Sci. 117, 4055-4066. https://doi.org/10.1242/jcs.01275

Cited by

  1. The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms vol.10, pp.1663-4365, 2019, https://doi.org/10.3389/fnagi.2018.00440
  2. Genetic Defects in Mitochondrial Dynamics in Caenorhabditis elegans Impact Ultraviolet C Radiation- and 6-hydroxydopamine-Induced Neurodegeneration vol.20, pp.13, 2017, https://doi.org/10.3390/ijms20133202
  3. Flavonoids mitigate neurodegeneration in aged Caenorhabditis elegans by mitochondrial uncoupling vol.8, pp.12, 2017, https://doi.org/10.1002/fsn3.1956
  4. The Mitochondrial Na + /Ca 2+ Exchanger Inhibitor CGP37157 Preserves Muscle Structure and Function to Increase Lifespan and Healthspan in Caenorhabditis elegans vol.12, pp.None, 2017, https://doi.org/10.3389/fphar.2021.695687
  5. Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans vol.10, pp.3, 2017, https://doi.org/10.3390/cells10030694