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Axons Degenerate in the Absence of Mitochondria in C. elegans

2014; Elsevier BV; Volume: 24; Issue: 7 Linguagem: Inglês

10.1016/j.cub.2014.02.025

1879-0445

Randi L. Rawson, Lung T. Yam, Robby M. Weimer, Eric G. Bend, Erika Hartwieg, H. Robert Horvitz, Scott G. Clark, Erik M. Jørgensen,

Genetic Neurodegenerative Diseases

Many neurodegenerative disorders are associated with mitochondrial defects [1Patten D.A. Germain M. Kelly M.A. Slack R.S. Reactive oxygen species: stuck in the middle of neurodegeneration.J. Alzheimers Dis. 2010; 20: S357-S367PubMed Google Scholar, 2Chang D.T.W. Rintoul G.L. Pandipati S. Reynolds I.J. Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons.Neurobiol. Dis. 2006; 22: 388-400Crossref PubMed Scopus (226) Google Scholar, 3Schon E.A. Przedborski S. Mitochondria: the next (neurode)generation.Neuron. 2011; 70: 1033-1053Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar]. Mitochondria can play an active role in degeneration by releasing reactive oxygen species and apoptotic factors [4Alvarez S. Moldovan M. Krarup C. Acute energy restriction triggers Wallerian degeneration in mouse.Exp. Neurol. 2008; 212: 166-178Crossref PubMed Scopus (32) Google Scholar, 5Lucius R. Sievers J. Postnatal retinal ganglion cells in vitro: protection against reactive oxygen species (ROS)-induced axonal degeneration by cocultured astrocytes.Brain Res. 1996; 743: 56-62Crossref PubMed Scopus (67) Google Scholar, 6Koeberle P.D. Ball A.K. Nitric oxide synthase inhibition delays axonal degeneration and promotes the survival of axotomized retinal ganglion cells.Exp. Neurol. 1999; 158: 366-381Crossref PubMed Scopus (104) Google Scholar, 7Shigenaga M.K. Hagen T.M. Ames B.N. Oxidative damage and mitochondrial decay in aging.Proc. Natl. Acad. Sci. USA. 1994; 91: 10771-10778Crossref PubMed Scopus (1829) Google Scholar]. Alternatively, mitochondria can protect axons from stress and insults, for example by buffering calcium [8Avery M.A. Rooney T.M. Pandya J.D. Wishart T.M. Gillingwater T.H. Geddes J.W. Sullivan P.G. Freeman M.R. WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering.Curr. Biol. 2012; 22: 596-600Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar]. Recent studies manipulating mitochondria lend support to both of these models [9Barrientos S.A. Martinez N.W. Yoo S. Jara J.S. Zamorano S. Hetz C. Twiss J.L. Alvarez J. Court F.A. Axonal degeneration is mediated by the mitochondrial permeability transition pore.J. Neurosci. 2011; 31: 966-978Crossref PubMed Scopus (175) Google Scholar, 10Keller L.C. Cheng L. Locke C.J. Müller M. Fetter R.D. Davis G.W. Glial-derived prodegenerative signaling in the Drosophila neuromuscular system.Neuron. 2011; 72: 760-775Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 11Fang Y. Soares L. Teng X. Geary M. Bonini N.M. A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity.Curr. Biol. 2012; 22: 590-595Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 12Iijima-Ando K. Sekiya M. Maruko-Otake A. Ohtake Y. Suzuki E. Lu B. Iijima K.M. Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer’s disease-related tau phosphorylation via PAR-1.PLoS Genet. 2012; 8: e1002918Crossref PubMed Scopus (97) Google Scholar, 13Kitay B.M. McCormack R. Wang Y. Tsoulfas P. Zhai R.G. Mislocalization of neuronal mitochondria reveals regulation of Wallerian degeneration and NMNAT/WLD(S)-mediated axon protection independent of axonal mitochondria.Hum. Mol. Genet. 2013; 22: 1601-1614Crossref PubMed Scopus (49) Google Scholar]. Here, we identify a C. elegans mutant, ric-7, in which mitochondria are unable to exit the neuron cell bodies, similar to the kinesin-1/unc-116 mutant. When axons lacking mitochondria are cut with a laser, they rapidly degenerate. Some neurons even spontaneously degenerate in ric-7 mutants. Degeneration can be suppressed by forcing mitochondria into the axons of the mutants. The protective effect of mitochondria is also observed in the wild-type: a majority of axon fragments containing a mitochondrion survive axotomy, whereas those lacking mitochondria degenerate. Thus, mitochondria are not required for axon degeneration and serve a protective role in C. elegans axons.