{"doi":"10.1016/j.jbc.2023.103018","title":"Mitochondrial respiration reduces exposure of the nucleus to oxygen","abstract":"The endosymbiotic theory posits that ancient eukaryotic cells engulfed O 2 -consuming prokaryotes, which protected them against O 2 toxicity. Previous studies have shown that cells lacking cytochrome c oxidase (COX), required for respiration, have increased DNA damage and reduced proliferation, which could be improved by reducing O 2 exposure. With recently developed fluorescence lifetime microscopy–based probes demonstrating that the mitochondrion has lower [O 2 ] than the cytosol, we hypothesized that the perinuclear distribution of mitochondria in cells may create a barrier for O 2 to access the nuclear core, potentially affecting cellular physiology and maintaining genomic integrity. To test this hypothesis, we utilized myoglobin-mCherry fluorescence lifetime microscopy O 2 sensors without subcellular targeting (\"cytosol\") or with targeting to the mitochondrion or nucleus for measuring their localized O 2 homeostasis. Our results showed that, similar to the mitochondria, the nuclear [O 2 ] was reduced by ∼20 to 40% compared with the cytosol under imposed O 2 levels of ∼0.5 to 18.6%. Pharmacologically inhibiting respiration increased nuclear O 2 levels, and reconstituting O 2 consumption by COX reversed this increase. Similarly, genetic disruption of respiration by deleting SCO2 , a gene essential for COX assembly, or restoring COX activity in SCO2 −/− cells by transducing with SCO2 cDNA replicated these changes in nuclear O 2 levels. The results were further supported by the expression of genes known to be affected by cellular O 2 availability. Our study reveals the potential for dynamic regulation of nuclear O 2 levels by mitochondrial respiratory activity, which in turn could affect oxidative stress and cellular processes such as neurodegeneration and aging.","journal":"Journal of Biological Chemistry","year":2023,"id":335942,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":458258,"name":"Rozhin Penjweini","orcid":null,"position":1,"is_corresponding":false},{"id":972722,"name":"Jin Ma","orcid":"0000-0001-6802-455X","position":2,"is_corresponding":false},{"id":458260,"name":"Greg Alspaugh","orcid":null,"position":3,"is_corresponding":false},{"id":457510,"name":"Alessio Andreoni","orcid":"0000-0003-4415-2770","position":4,"is_corresponding":false},{"id":244425,"name":"Young‐Chae Kim","orcid":"0000-0002-5130-4413","position":5,"is_corresponding":false},{"id":383917,"name":"Pingyuan Wang","orcid":"0009-0005-0368-5070","position":6,"is_corresponding":false},{"id":438071,"name":"Jay R. Knutson","orcid":"0000-0001-9990-1738","position":7,"is_corresponding":false},{"id":247630,"name":"Paul M. Hwang","orcid":"0000-0002-5976-7834","position":8,"is_corresponding":false},{"id":669638,"name":"Mateus Prates Mori","orcid":"0000-0003-1349-6378","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:10:02.777338Z","pmid":"36796514","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":[]}