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In hypoxia, neuronal ATP production is impaired, ATP-dependent ion pumping is reduced, transmembrane ion gradients are dysregulated, and intracellular Ca2+ concentration ([Ca2+]i) increases enough to trigger excitotoxic cell death. Central neurons of the common goldfish (Carassius auratus) are hypoxia tolerant, but little is known about how goldfish retinas withstand hypoxia. To study the cellular mechanisms of hypoxia tolerance, we isolated retinal interneurons (horizontal cells; HCs), and measured [Ca2+]i with Fura-2. Goldfish HCs maintained [Ca2+]i throughout 1\u2005h of hypoxia, whereas [Ca2+]i increased irreversibly in HCs of the hypoxia-sensitive rainbow trout (Oncorhynchus mykiss) with just 20\u2005min of hypoxia. Our results suggest mitochondrial ATP-dependent K+ channels (mKATP) are necessary to stabilize [Ca2+]i throughout hypoxia. In goldfish HCs, [Ca2+]i increased when mKATP channels were blocked with glibenclamide or 5-hydroxydecanoic acid, whereas the mKATP channel agonist diazoxide prevented [Ca2+]i from increasing in hypoxia in trout HCs. We found that hypoxia protects against increases in [Ca2+]i in goldfish HCs via mKATP channels. Glycolytic inhibition with 2-deoxyglucose increased [Ca2+]i, which was rescued by hypoxia in a mKATP channel-dependent manner. We found no evidence of plasmalemmal KATP channels in patch-clamp experiments. Instead, we confirmed the involvement of KATP in mitochondria with TMRE imaging, as hypoxia rapidly (&amp;lt;5\u2005min) depolarized mitochondria in a mKATP channel-sensitive manner. We conclude that mKATP channels initiate a neuroprotective pathway in goldfish HCs to maintain [Ca2+]i and avoid excitotoxicity in hypoxia. This model provides novel insight into the cellular mechanisms of hypoxia tolerance in the retina.<\/jats:p>","DOI":"10.1242\/jeb.242634","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T11:07:56Z","timestamp":1629198476000},"source":"Crossref","is-referenced-by-count":12,"title":["Mitochondrial KATP channels stabilize intracellular Ca2+ during hypoxia in retinal horizontal cells of goldfish (<i>Carassius auratus<\/i>)"],"prefix":"10.1242","volume":"224","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5239-6607","authenticated-orcid":false,"given":"Michael W.","family":"Country","sequence":"first","affiliation":[{"name":"Department of Biology, University of Ottawa, Ottawa, ON, CanadaK1N 6N5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2111-1570","authenticated-orcid":false,"given":"Michael G.","family":"Jonz","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, Ottawa, ON, CanadaK1N 6N5"},{"name":"Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, CanadaK1H 8M5"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"2021092212273032900_JEB242634C1","doi-asserted-by":"publisher","first-page":"S158","DOI":"10.1139\/y92-257","article-title":"Energy requirements of CNS cells as related to their function and to their vulnerability to ischemia: a commentary based on studies on retina","volume":"70","author":"Ames","year":"1992","journal-title":"Can. 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