Anoxia-Reoxygenation Regulates Mitochondrial Dynamics through the Hypoxia Response Pathway, SKN-1Nrf, and Stomatin-Like Protein STL-1SLP-2.docVIP

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Anoxia-Reoxygenation Regulates Mitochondrial Dynamics through the Hypoxia Response Pathway, SKN-1Nrf, and Stomatin-Like Protein STL-1SLP-2.doc

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Anoxia-Reoxygenation Regulates Mitochondrial Dynamics through the Hypoxia Response Pathway, SKN-1Nrf, and Stomatin-Like Protein STL-1SLP-2

Anoxia-Reoxygenation Regulates Mitochondrial Dynamics through the Hypoxia Response Pathway, SKN-1/Nrf, and Stomatin-Like Protein STL-1/SLP-2 PiyaGhose1,2.,EunChanPark1.,AlexandraTabakin1,NathalySalazar-Vasquez1,3,ChristopherRongo1* 1TheWaksmanInstitute,DepartmentofGenetics,RutgersTheStateUniversityofNewJersey,Piscataway,NewJersey,UnitedStatesofAmerica,2TheGraduateProgram inNeuroscience,RutgersTheStateUniversityofNewJersey,Piscataway,NewJersey,UnitedStatesofAmerica,3TheGraduatePrograminGeneticsandMicrobiology, RutgersTheStateUniversityofNewJersey,Piscataway,NewJersey,UnitedStatesofAmerica Abstract Manyaerobicorganismsencounteroxygen-deprivedenvironmentsandthusmusthaveadaptivemechanismstosurvive suchstress.Itisimportanttounderstandhowmitochondriarespondtooxygendeprivationgiventhecriticalroletheyplay inusingoxygentogeneratecellularenergy.HereweexaminemitochondrialstressresponseinC.elegans,whichadaptto extreme oxygen deprivation (anoxia, less than 0.1% oxygen) by entering into a reversible suspended animation state of locomotory arrest. We show that neuronal mitochondria undergo DRP-1-dependent fission in response to anoxia and undergo refusion upon reoxygenation. The hypoxia response pathway, including EGL-9 and HIF-1, is not required for anoxia-induced fission, but does regulate mitochondrial reconstitution during reoxygenation. Mutants for egl-9 exhibit a rapid refusion of mitochondria and a rapid behavioral recovery from suspended animation during reoxygenation; both phenotypesrequireHIF-1.Mitochondriaaresignificantlylargerinegl-9mutantsafterreoxygenation,aphenotypesimilarto stress-induced mitochondria hyperfusion (SIMH). Anoxia results in mitochondrial oxidative stress, and the oxidative response factor SKN-1/Nrf is required for both rapid mitochondrial refusion and rapid behavioral recovery during reoxygenation.Inresponsetoanoxia,SKN-1promotestheexpressionofthemitochondrialresidentproteinStomatin-like1 (STL-1),whichhelpsfacilitatemitochondrialdynamicsfollowingan