{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:08:58Z","timestamp":1789031338703,"version":"build-2803163510"},"reference-count":27,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MitoSynergy"},{"name":"Autism Discovery and Treatment Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Copper is a redox-active transition metal that is essential for the assembly and catalytic function of cytochrome c oxidase (Complex IV), the terminal enzyme of the mitochondrial electron transport chain and a principal site of physiological oxygen reduction. Elevated Complex IV activity and respiratory chain uncoupling are among the most consistently replicated biological findings in autism spectrum disorder (ASD), yet the interaction between mitochondrial copper delivery, respiration, and cellular oxidant handling in ASD has not been systematically defined. We treated dermal fibroblasts from 9 children with ASD and 10 typically developing controls with the copper(I)\u2013niacin complex Cunermuspir (0, 50, or 100 \u00b5M for 1 or 24 h exposure) and challenged them with graded concentrations (0\u20135.0 \u00b5M) of the redox-cycling agent 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). Mitochondrial respiration was profiled by Seahorse XF respirometry (2133 observations across 28 experiments), and cellular reactive oxygen species (CellROX\u2122 Green) and mitochondrial mass\/polarization (MitoTracker\u2122 Deep Red) were quantified by fluorescence imaging. ASD fibroblasts displayed a hypermetabolic, uncoupled respiratory phenotype (~73% higher baseline respiration; ~109% higher proton leak; reduced coupling efficiency). Linear mixed models with polynomial dose terms revealed significant ASD \u00d7 Cunermuspir complex interactions (ASD \u00d7 Cunermuspir and\/or their higher-order interactions with DMNQ and treatment) for four respiratory parameters. ASD cells exhibited lower steady-state oxidation-dependent CellROX\u2122 Green fluorescence than controls despite greater respiratory uncoupling, as well as lower steady-state MitoTracker\u2122 Deep Red fluorescence; Cunermuspir reshaped the MitoTracker\u2122 DMNQ dose\u2013response in an ASD-selective manner. These findings identify the Cunermuspir-associated modulation of the ASD mitochondrial and oxidant handling phenotype and motivate further mechanistic and translational evaluation.<\/jats:p>","DOI":"10.3390\/antiox15091147","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T08:07:41Z","timestamp":1789027661000},"page":"1147","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cunermuspir, a Copper(I)\u2013Niacin Complex, Modulates Mitochondrial Respiration and Cellular Oxidant Handling in Fibroblasts from Children with Autism Spectrum Disorder"],"prefix":"10.3390","volume":"15","author":[{"given":"Sophie","family":"Wallace","sequence":"first","affiliation":[{"name":"Autism Discovery and Treatment Foundation, Phoenix, AZ 85024, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Spencer","family":"Lawes","sequence":"additional","affiliation":[{"name":"Autism Discovery and Treatment Foundation, Phoenix, AZ 85024, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3497-1895","authenticated-orcid":false,"given":"Adrienne C.","family":"Scheck","sequence":"additional","affiliation":[{"name":"Autism Discovery and Treatment Foundation, Phoenix, AZ 85024, USA"},{"name":"Department of Basic Medical Sciences, University of Arizona College of Medicine\u2014Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Richard E.","family":"Frye","sequence":"additional","affiliation":[{"name":"Autism Discovery and Treatment Foundation, Phoenix, AZ 85024, USA"},{"name":"Rossignol Medical Center, Phoenix, AZ 85018, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"118867","DOI":"10.1016\/j.bbamcr.2020.118867","article-title":"Getting Out What You Put In: Copper in Mitochondria and Its Impacts on Human Disease","volume":"1868","author":"Cobine","year":"2021","journal-title":"Biochim. 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