The innate immune response mounts a defense against foreign invaders and declines with age. An inappropriate induction of this response can cause diseases. Previous studies showed that mitochondria can be repurposed to promote inflammatory signaling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1, a gene required for mitochondrial health, cause Parkinson’s disease, and Drosophila melanogaster pink1 mutants accumulate damaged mitochondria. Here, we show that defective mitochondria in pink1 mutants activate Relish targets and demonstrate that inflammatory signaling causes age-dependent intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells, metabolic reprogramming and neurotoxicity. We found that Relish signaling is activated downstream of a pathway stimulated by cytosolic DNA. Suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and is neuroprotective. We thus conclude that gut–brain communication modulates neurotoxicity in a fly model of Parkinson’s disease through a mechanism involving mitochondrial dysfunction.
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Source date files, including raw numerical data, descriptive statistics, normality tests and statistical analysis used in the manuscript, are available in our GitHub repository at github.com/M1gus/Gut-brain. Microarray data, with detailed descriptions of the experimental protocols, and raw data were deposited in ArrayExpress under accession no. E-MTAB-6210. Proteomics data was deposited at the ProteomeXchange Consortium with dataset identifier PXD030979. All other data are available upon reasonable request.
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Proteomics analysis was performed at the Cambridge Centre for Proteomics by R. Feret, M. Deery and Y. Umrania. We thank the Vienna Drosophila RNAi Center, Bloomington Drosophila Stock Center, J. Cordero, A. Telemans, A. Franz and E. Rosato for provision of fly stocks; the Fly Facility, Department of Genetics, University of Cambridge, for maintaining the stocks; and T. Ashby and M. Patel for preparing the fly food. This work was funded by the UK Medical Research Council intramural project MC_UU_00025/3 (no. RG94521) to L.M.M. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
The authors declare no competing interests.
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Fedele, G., Loh, S.H.Y., Celardo, I. et al. Suppression of intestinal dysfunction in a Drosophila model of Parkinson’s disease is neuroprotective. Nat Aging 2, 317–331 (2022). https://doi.org/10.1038/s43587-022-00194-z
Nature Aging (2022)