title: The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans.
abstract: The mitochondrial unfolded protein response (UPRmt) is a surveillance pathway that defends proteostasis in the "powerhouse" of the cell. Activation of the UPRmt protects against stresses imposed by reactive oxygen species, respiratory chain deficits, and pathologic bacteria. Consistent with the UPRmt's role in adaption, we found that either its pharmacological or genetic activation by ethidium bromide (EtBr) or RNAi of the mitochondrial AAA-protease spg-7 was sufficient to reduce death in an anoxia-based Caenorhabditis elegans model of ischemia-reperfusion injury. The UPRmt-specific transcription factor atfs-1 was necessary for protection and atfs-1 gain-of-function (gf) mutants were endogenously protected from both death and dysfunction. Neurons exhibited less axonal degeneration following non-lethal anoxia-reperfusion (A-R) when the UPRmt was pre-activated, and consistent with the concept of mitochondrial stress leading to cell non-autonomous (ie. "remote") effects, we found that restricted activation of the UPRmt in neurons decreased A-R death. However, expression of the atfs-1(gf) mutant in neurons, which resulted in a robust activation of a neuronal UPRmt, did not upregulate the UPRmt in distal tissues, nor did it protect the worms from A-R toxicity. These findings suggest that remote signaling requires additional component(s) acting downstream of de facto mitochondrial stress.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Salvador
authors.initials: S
authors.lastname: Peña
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Teresa
authors.initials: T
authors.lastname: Sherman
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York, United States of America.|Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.|Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Nehrke
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D015427:Reperfusion Injury / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C548052:ATFS-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D014157:Transcription Factors; D008666:Metalloendopeptidases; C114583:m-AAA proteases