{"doi":"10.1016/j.mito.2025.102004","title":"Sex-dependent adaptations in heart mitochondria from transgenic mice overexpressing cytochrome b5 reductase-3","abstract":"• The heart is a valuable model to investigate cell-autonomous metabolic regulation induced by CYB5R3 overexpression. • CYB5R3 overexpression downregulates electron transport chain complexes markers in male heart without decreasing oxygen consumption capacity. • CYB5R3 overexpression increases the size and abundance of cardiomyocytes mitochondria in males. • Overexpression of CYB5R3 decreases thickness and preserves the length of mitochondria-endoplasmic reticulum contact sites in male heart. • CYB5R3 overexpression promotes cardiac mitochondrial fatty acid oxidation, particularly in males. Cytochrome b 5 reductase 3 (CYB5R3) overexpression upregulates mitochondrial biogenesis, function, and abundance in skeletal muscle and kidneys, and mimics some of the salutary effects of calorie restriction, with the most striking effects being observed in females. We aimed to investigate the mitochondrial adaptations prompted by CYB5R3 overexpression in the heart, an organ surprisingly overlooked in studies focused on this long-lived transgenic model despite the critical role played by CYB5R3 in supporting cardiomyocytes mitochondrial respiration. Given that CYB5R3 effects have been found to be sex-dependent, we focused our research on both males and females. CYB5R3 was efficiently overexpressed in cardiac tissue from transgenic mice, without any difference between sexes. The abundance of electron transport chain complexes markers and cytochrome c was higher in males than in females. CYB5R3 overexpression downregulated the levels of complexes markers in males but not females, without decreasing oxygen consumption capacity. CYB5R3 increased the size and abundance of cardiomyocytes mitochondria, and reduced thickness and preserved the length of mitochondria-endoplasmic reticulum contact sites in heart from males but not females. Metabolic changes were also highlighted in transgenic mice, with an upregulation of fatty acid oxidation markers, particularly in males. Our results support that CYB5R3 overexpression upregulates markers consistent with enhanced mitochondrial function in the heart, producing most of these actions in males, with illustrates the complexity of the CYB5R3-overexpressing transgenic model.","journal":"Mitochondrion","year":2025,"id":540022,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":675622,"name":"José A. González‐Reyes","orcid":"0000-0003-1918-5490","position":1,"is_corresponding":false},{"id":873764,"name":"Sandra Rodríguez-López","orcid":"0000-0002-5088-6458","position":2,"is_corresponding":false},{"id":706046,"name":"Miguel Calvo‐Rubio","orcid":"0000-0003-3760-4118","position":3,"is_corresponding":false},{"id":1290185,"name":"Pilar Calero-Rodríguez","orcid":null,"position":4,"is_corresponding":false},{"id":258549,"name":"Rafael de Cabo","orcid":"0000-0003-2830-5693","position":5,"is_corresponding":false},{"id":1289723,"name":"María I. Burón","orcid":"0000-0003-2923-2684","position":6,"is_corresponding":false},{"id":472873,"name":"José M. Villalba","orcid":"0000-0001-8554-3802","position":7,"is_corresponding":false},{"id":1289719,"name":"Luz Marina Sánchez‐Mendoza","orcid":"0000-0002-1422-4246","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:52:34.520788Z","pmid":"39793940","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":[]}