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Female dopamine (DA) neurons are more resilient via mechanisms that remain unclear. Here, we discovered key sex and regional differences in mitochondrial generation of cytotoxic reactive oxygen species (ROS) and their implications for DA neuron resilience using the <jats:italic>Drosophila<\/jats:italic> model. While aging raised mitochondrial ROS in DA neurons of both sexes, we observed a sexually dimorphic response in the paraquat (PQ) PD model. DA neuron knockdown of the <jats:italic>Drosophila<\/jats:italic> vesicular glutamate transporter (dVGLUT) increased mitochondrial ROS only in males, leaving females protected. Cell depolarization, a physiological stressor, similarly raised mitochondrial ROS in DA neurons selectively in males following dVGLUT knockdown. We also identified dVGLUT\u2010dependent changes in intracellular ATP in both sexes. Overall, we discovered sexually dimorphic relationships between dVGLUT, ATP synthesis, and ROS generation in DA neurons, providing a mechanistic basis for DA neuron resilience.<\/jats:p>","DOI":"10.1111\/acel.70096","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T09:18:13Z","timestamp":1748337493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>dVGLUT<\/scp> Is a Mediator of Sex Differences in Dopamine Neuron Mitochondrial Function Across Aging and in a Parkinson's Disease Model"],"prefix":"10.1111","volume":"24","author":[{"given":"Silas A.","family":"Buck","sequence":"first","affiliation":[{"name":"Center for Neuroscience University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Mabry","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenzin","family":"Kunkhyen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1140-769X","authenticated-orcid":false,"given":"Zilu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie A.","family":"Rubin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinting","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire E. 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