{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:54:09Z","timestamp":1782280449946,"version":"3.54.5"},"posted":{"date-parts":[[2021,11,30]]},"group-title":"Neuroscience","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council of Taiwan","doi-asserted-by":"crossref","award":["MOST 111-2320-B-110-003-MY2"],"award-info":[{"award-number":["MOST 111-2320-B-110-003-MY2"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS125788, NS135793, NS127392, HD109025, NS099261, NS120481, and NS125677"],"award-info":[{"award-number":["NS125788, NS135793, NS127392, HD109025, NS099261, NS120481, and NS125677"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000001","name":"U.S. National Science Foundation","doi-asserted-by":"crossref","award":["NSF CAREER 202988"],"award-info":[{"award-number":["NSF CAREER 202988"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in the brain by impairing blood oxygen supply and the cerebral metabolic rate of oxygen (CMRO\n                  <jats:sub>2<\/jats:sub>\n                  ), is a leading cause of neonatal brain injury. However, it is unclear how post-HI hypothermia helps to restore the balance, as cooling reduces CMRO\n                  <jats:sub>2<\/jats:sub>\n                  . Also, how transient HI leads to secondary energy failure (SEF) in neonatal brains remains elusive. Using photoacoustic microscopy, we examined the effects of HI on CMRO\n                  <jats:sub>2<\/jats:sub>\n                  in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO\n                  <jats:sub>2<\/jats:sub>\n                  , it sparks a prolonged CMRO\n                  <jats:sub>2<\/jats:sub>\n                  -surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis\u2014indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO\n                  <jats:sub>2<\/jats:sub>\n                  -surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hours post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO\n                  <jats:sub>2<\/jats:sub>\n                  -surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO\n                  <jats:sub>2<\/jats:sub>\n                  -measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.\n                <\/jats:p>","DOI":"10.1101\/2021.11.29.470404","type":"posted-content","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T18:20:40Z","timestamp":1638296440000},"source":"Crossref","is-referenced-by-count":1,"title":["Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia"],"prefix":"10.64898","author":[{"given":"Naidi","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Yo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Ru","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Fugate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marchelle R.","family":"Smucker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Min","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1005-4013","authenticated-orcid":false,"given":"P. Ellen","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M.","family":"Lindquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yi","family":"Kuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100113500512000_2021.11.29.470404v3.1","doi-asserted-by":"publisher","DOI":"10.1053\/j.nainr.2011.07.004"},{"key":"2025100113500512000_2021.11.29.470404v3.2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1542\/peds.92.1.99","article-title":"Cerebral oxygen metabolism in 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