{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:23:51Z","timestamp":1787066631180,"version":"build-2736575974"},"reference-count":44,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T00:00:00Z","timestamp":1693872000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["#04229"],"award-info":[{"award-number":["#04229"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["NSF2014862\u2010UTA20\u2010000890"],"award-info":[{"award-number":["NSF2014862\u2010UTA20\u2010000890"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,11]]},"abstract":"\n Abstract<\/jats:title>\n \n Deleterious Ca\n 2+<\/jats:sup>\n accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia\u2010mediated increases in cytosolic Ca\n 2+<\/jats:sup>\n are retarded in hypoxia\u2010tolerant naked mole\u2010rat brain. We hypothesized that naked mole\u2010rat brain mitochondria have an enhanced capacity to buffer exogenous Ca\n 2+<\/jats:sup>\n and examined Ca\n 2+<\/jats:sup>\n handling in naked mole\u2010rat cortical tissue. We report that naked mole\u2010rat brain mitochondria buffer >2\u2010fold more exogenous Ca\n 2+<\/jats:sup>\n than mouse brain mitochondria, and that the half\u2010maximal inhibitory concentration (IC\n 50<\/jats:sub>\n ) at which Ca\n 2+<\/jats:sup>\n inhibits aerobic oxidative phosphorylation is >2\u2010fold higher in naked mole\u2010rat brain. The primary driving force of Ca\n 2+<\/jats:sup>\n uptake is the mitochondrial membrane potential (\u0394\u03c8\n m<\/jats:sub>\n ), and the IC\n 50<\/jats:sub>\n at which Ca\n 2+<\/jats:sup>\n decreases \u0394\u03c8\n m<\/jats:sub>\n is \u223c4\u2010fold higher in naked mole\u2010rat than mouse brain. The ability of naked mole\u2010rat brain mitochondria to safely retain large volumes of Ca\n 2+<\/jats:sup>\n may be due to ultrastructural differences that support the uptake and physical storage of Ca\n 2+<\/jats:sup>\n in mitochondria. Specifically, and relative to mouse brain, naked mole\u2010rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca\n 2+<\/jats:sup>\n management. We propose that excessive Ca\n 2+<\/jats:sup>\n influx into naked mole\u2010rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca\n 2+<\/jats:sup>\n overload and may thus contribute to the hypoxia and ischaemia\u2010tolerance of naked mole\u2010rat brain.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Unregulated Ca\n 2+<\/jats:sup>\n influx is a hallmark of hypoxic brain death; however, hypoxia\u2010mediated Ca\n 2+<\/jats:sup>\n influx into naked mole\u2010rat brain is markedly reduced relative to mice.\n <\/jats:p>\n <\/jats:list-item>\n \n \n This is important because naked mole\u2010rat brain is robustly tolerant against\n in vitro<\/jats:italic>\n hypoxia, and because Ca\n 2+<\/jats:sup>\n is a key driver of hypoxic cell death in brain.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We show that in hypoxic naked mole\u2010rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca\n 2+<\/jats:sup>\n stress.\n <\/jats:p>\n <\/jats:list-item>\n \n \n This is due to mitochondrial buffering of exogenous Ca\n 2+<\/jats:sup>\n and is driven by a mitochondrial membrane potential\u2010dependant mechanism.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The unique ultrastructure of naked mole\u2010rat brain mitochondria, as a large physical storage space, may support increased Ca\n 2+<\/jats:sup>\n buffering and thus hypoxia\u2010tolerance.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp285002","type":"journal-article","created":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T05:44:52Z","timestamp":1693892692000},"page":"5685-5698","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Enhanced mitochondrial buffering prevents Ca\n 2+<\/sup>\n overload in naked mole\u2010rat brain"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5251-640X","authenticated-orcid":false,"given":"Hang","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Biology University of Ottawa Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Perkins","sequence":"additional","affiliation":[{"name":"National Center for Microscopy and Imaging Research, Department of Neurosciences University of California San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeyeon","family":"Ju","sequence":"additional","affiliation":[{"name":"National Center for Microscopy and Imaging Research, Department of Neurosciences University of California San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keunyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"National Center for Microscopy and Imaging Research, Department of Neurosciences University of California San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark H.","family":"Ellisman","sequence":"additional","affiliation":[{"name":"National Center for Microscopy and Imaging Research, Department of Neurosciences University of California San Diego CA USA"},{"name":"Department of Neurosciences University of California at San Diego School of Medicine San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-9555","authenticated-orcid":false,"given":"Matthew E.","family":"Pamenter","sequence":"additional","affiliation":[{"name":"Department of Biology University of Ottawa Ottawa Ontario Canada"},{"name":"University of Ottawa Brain and Mind Research Institute Ottawa Ontario 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