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However, a growing body of evidence indicates that it is contributing to the global decline in population sizes of many beneficial insect species. Spinosad emerged as an organic alternative to synthetic insecticides and is considered less harmful to beneficial insects, yet its mode of action remains unclear. Using\n                    <jats:italic>Drosophila<\/jats:italic>\n                    , we show that low doses of spinosad antagonize its neuronal target, the nicotinic acetylcholine receptor subunit alpha 6 (nAChR\u03b16), reducing the cholinergic response. We show that the nAChR\u03b16 receptors are transported to lysosomes that become enlarged and increase in number upon low doses of spinosad treatment. Lysosomal dysfunction is associated with mitochondrial stress and elevated levels of reactive oxygen species (ROS) in the central nervous system where nAChR\u03b16 is broadly expressed. ROS disturb lipid storage in metabolic tissues in an nAChR\u03b16-dependent manner. Spinosad toxicity is ameliorated with the antioxidant N-acetylcysteine amide. Chronic exposure of adult virgin females to low doses of spinosad leads to mitochondrial defects, severe neurodegeneration, and blindness. These deleterious effects of low-dose exposures warrant rigorous investigation of its impacts on beneficial insects.\n                  <\/jats:p>","DOI":"10.7554\/elife.73812","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T08:15:46Z","timestamp":1643616946000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.73812","source":"Crossref","is-referenced-by-count":63,"title":["Low doses of the organic insecticide spinosad trigger lysosomal defects, elevated ROS, lipid dysregulation, and neurodegeneration in flies"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4783-9025","authenticated-orcid":true,"given":"Felipe","family":"Martelli","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ej9dk98","id-type":"ROR","asserted-by":"publisher"}],"name":"School of BioSciences, The University of Melbourne","place":["Melbourne, 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