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.
Keywords:
ATF-7; PINK-1; autophagy; complex I; innate immune response; mitochondria; neurodegeneration; non-autonomous; p38MAPK; rotenone.
Published by Elsevier Inc.
MeSH terms
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Activating Transcription Factors / genetics*
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Activating Transcription Factors / immunology
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Animals
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / immunology*
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Caenorhabditis elegans Proteins / genetics*
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Caenorhabditis elegans Proteins / immunology
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Dopamine / metabolism
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / immunology*
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Dopaminergic Neurons / pathology
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Electron Transport Complex I / deficiency
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Electron Transport Complex I / genetics*
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Electron Transport Complex I / immunology
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Epithelial Cells / drug effects
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Epithelial Cells / immunology
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Epithelial Cells / pathology
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Gastrointestinal Tract / drug effects
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Gastrointestinal Tract / immunology
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Gastrointestinal Tract / pathology
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Gene Expression Regulation
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Immunity, Innate
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Mitochondria / drug effects
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Mitochondria / immunology*
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Mitochondria / pathology
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Mitophagy / drug effects
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Mitophagy / genetics
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Nerve Degeneration / chemically induced
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Nerve Degeneration / genetics
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Nerve Degeneration / immunology
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Rotenone / toxicity
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / genetics*
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p38 Mitogen-Activated Protein Kinases / immunology
Substances
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ATF-7 protein, C elegans
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Activating Transcription Factors
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Caenorhabditis elegans Proteins
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Rotenone
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p38 Mitogen-Activated Protein Kinases
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Electron Transport Complex I
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Dopamine