title: The Mitochondria-Regulated Immune Pathway Activated in the C. elegans Intestine Is Neuroprotective.
abstract: Immunological mediators that originate outside the nervous system can affect neuronal health. However, their roles in neurodegeneration remain largely unknown. Here, we show that the p38MAPK-mediated immune pathway activated in intestinal cells of Caenorhabditis elegans upon mitochondrial dysfunction protects neurons in a cell-non-autonomous fashion. Specifically, mitochondrial complex I dysfunction induced by rotenone activates the p38MAPK/CREB/ATF-7-dependent innate immune response pathway in intestinal cells of C. elegans. Activation of p38MAPK in the gut is neuroprotective. Enhancing the p38MAPK-mediated immune pathway in intestinal cells alone suppresses rotenone-induced dopaminergic neuron loss, while downregulating it in the intestine exacerbates neurodegeneration. The p38MAPK/ATF-7 immune pathway modulates autophagy and requires autophagy and the PTEN-induced putative kinase PINK-1 for conferring neuroprotection. Thus, mitochondrial damage induces the clearance of mitochondria by the immune pathway, protecting the organism from the toxic effects of mitochondrial dysfunction. We propose that mitochondria are subject to constant surveillance by innate immune mechanisms.
authors.affiliation: Department of Biology, Aging Mind and Brain Initiative, 143 Biology Building East, 338 BBE, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Madhusudana Rao
authors.initials: MR
authors.lastname: Chikka
authors.affiliation: Department of Biology, Aging Mind and Brain Initiative, 143 Biology Building East, 338 BBE, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Charumathi
authors.initials: C
authors.lastname: Anbalagan
authors.affiliation: Department of Biology, Aging Mind and Brain Initiative, 143 Biology Building East, 338 BBE, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Dvorak
authors.affiliation: Department of Biology, Aging Mind and Brain Initiative, 143 Biology Building East, 338 BBE, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Dombeck
authors.affiliation: Department of Biology, Aging Mind and Brain Initiative, 143 Biology Building East, 338 BBE, University of Iowa, Iowa City, IA 52242, USA. Electronic address: veena-prahlad@uiowa.edu.
authors.forename: Veena
authors.initials: V
authors.lastname: Prahlad
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000276:immunology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D012402:Rotenone / Q000633:toxicity; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000276:immunology
chemical_list: C551311:ATF-7 protein, C elegans; D051696:Activating Transcription Factors; D029742:Caenorhabditis elegans Proteins; D012402:Rotenone; D048051:p38 Mitogen-Activated Protein Kinases; D042967:Electron Transport Complex I; D004298:Dopamine
keywords: ATF-7; PINK-1; autophagy; complex I; innate immune response; mitochondria; neurodegeneration; non-autonomous; p38MAPK; rotenone