{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T22:37:32Z","timestamp":1767911852673,"version":"3.49.0"},"reference-count":87,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T00:00:00Z","timestamp":1591142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["RO1 ES010563"],"award-info":[{"award-number":["RO1 ES010563"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["RO1 ES016931"],"award-info":[{"award-number":["RO1 ES016931"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["F31 ES028084"],"award-info":[{"award-number":["F31 ES028084"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Manganese (Mn) is an essential metal, but excessive exposures have been well-documented to culminate in neurotoxicity. Curiously, the precise mechanisms of Mn neurotoxicity are still unknown. One hypothesis suggests that Mn exerts its toxicity by inhibiting mitochondrial function, which then (if exposure levels are high and long enough) leads to cell death. Here, we used a Huntington\u2019s disease cell model with known differential sensitivities to manganese\u2014STHdhQ7\/Q7 and STHdhQ111\/Q111 cells\u2014to examine the effects of acute Mn exposure on mitochondrial function. We determined toxicity thresholds for each cell line using both changes in cell number and caspase-3\/7 activation. We used a range of acute Mn exposures (0\u2013300\u2009\u00b5M), both above and below the cytotoxic threshold, to evaluate mitochondria-associated metabolic balance, mitochondrial respiration, and substrate dependence. In both cell lines, we observed no effect on markers of mitochondrial function at subtoxic Mn exposures (below detectable levels of cell death), yet at supratoxic exposures (above detectable levels of cell death) mitochondrial function significantly declined. We validated these findings in primary striatal neurons. In cell lines, we further observed that subtoxic Mn concentrations do not affect glycolytic function or major intracellular metabolite quantities. These data suggest that in this system, Mn exposure impairs mitochondrial function only at concentrations coincident with or above the initiation of cell death and is not consistent with the hypothesis that mitochondrial dysfunction precedes or induces Mn cytotoxicity.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa079","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T19:26:34Z","timestamp":1590780394000},"page":"446-459","source":"Crossref","is-referenced-by-count":27,"title":["Manganese-induced Mitochondrial Dysfunction Is Not Detectable at Exposures Below the Acute Cytotoxic Threshold in Neuronal Cell Types"],"prefix":"10.1093","volume":"176","author":[{"given":"Emily B","family":"Warren","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miles R","family":"Bryan","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232"},{"name":"Department of Biochemistry, Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Morcillo","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keisha N","family":"Hardeman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232"},{"name":"Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Aschner","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8728-3346","authenticated-orcid":false,"given":"Aaron B","family":"Bowman","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232"},{"name":"Department of Biochemistry, Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,6,3]]},"reference":[{"key":"2020081005564646000_kfaa079-B1","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.neulet.2013.08.061","article-title":"Manganese induces mitochondrial dynamics impairment and apoptotic cell death: A study in human Gli36 cells","volume":"554","author":"Alaimo","year":"2013","journal-title":"Neurosci. 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