{"doi":"10.7554/elife.100129","title":"Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia","abstract":"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 2 ), 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 2 . 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 2 in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO 2 , it sparks a prolonged CMRO 2 -surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis—indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO 2 -surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hr post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO 2 -surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO 2 measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.","journal":"eLife","year":2024,"id":491954,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1382,"name":"Yu Sun","orcid":"0000-0002-6608-1347","position":1,"is_corresponding":false},{"id":473756,"name":"Rui Cao","orcid":"0000-0003-4444-7528","position":2,"is_corresponding":false},{"id":262570,"name":"Hong‐Ru Chen","orcid":"0000-0001-9016-2190","position":3,"is_corresponding":false},{"id":822692,"name":"Yiming Wang","orcid":"0000-0003-0513-9039","position":4,"is_corresponding":false},{"id":513073,"name":"Elizabeth M. Fugate","orcid":"0009-0003-0629-7183","position":5,"is_corresponding":false},{"id":265102,"name":"Marchelle R. Smucker","orcid":null,"position":6,"is_corresponding":false},{"id":262572,"name":"Yi-Min Kuo","orcid":"0000-0002-7949-6664","position":7,"is_corresponding":false},{"id":244777,"name":"P. Ellen Grant","orcid":"0000-0003-1005-4013","position":8,"is_corresponding":false},{"id":513074,"name":"Diana M. Lindquist","orcid":"0000-0002-6997-0350","position":9,"is_corresponding":false},{"id":1175864,"name":"Chia‐Yi Kuan","orcid":null,"position":10,"is_corresponding":false},{"id":475501,"name":"Song Hu","orcid":"0000-0002-5760-8012","position":11,"is_corresponding":false},{"id":820668,"name":"Naidi Sun","orcid":"0000-0002-2054-0392","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:08:49.768795Z","pmid":"41460247","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}