{"doi":"10.1016/j.jbc.2023.104708","title":"Mitochondrial membrane potential instability on reperfusion after ischemia does not depend on mitochondrial Ca2+ uptake","abstract":"Physiologic Ca 2+ entry via the Mitochondrial Calcium Uniporter (MCU) participates in energetic adaption to workload but may also contribute to cell death during ischemia/reperfusion (I/R) injury. The MCU has been identified as the primary mode of Ca 2+ import into mitochondria. Several groups have tested the hypothesis that Ca 2+ import via MCU is detrimental during I/R injury using genetically-engineered mouse models, yet the results from these studies are inconclusive. Furthermore, mitochondria exhibit unstable or oscillatory membrane potentials (ΔΨ m ) when subjected to stress, such as during I/R, but it is unclear if the primary trigger is an excess influx of mitochondrial Ca 2+ (mCa 2+ ), reactive oxygen species (ROS) accumulation, or other factors. Here, we critically examine whether MCU-mediated mitochondrial Ca 2+ uptake during I/R is involved in ΔΨ m instability, or sustained mitochondrial depolarization, during reperfusion by acutely knocking out MCU in neonatal mouse ventricular myocyte (NMVM) monolayers subjected to simulated I/R. Unexpectedly, we find that MCU knockout does not significantly alter mCa 2+ import during I/R, nor does it affect ΔΨ m recovery during reperfusion. In contrast, blocking the mitochondrial sodium-calcium exchanger (mNCE) suppressed the mCa 2+ increase during Ischemia but did not affect ΔΨ m recovery or the frequency of ΔΨ m oscillations during reperfusion, indicating that mitochondrial ΔΨ m instability on reperfusion is not triggered by mCa 2+ . Interestingly, inhibition of mitochondrial electron transport or supplementation with antioxidants stabilized I/R-induced ΔΨ m oscillations. The findings are consistent with mCa 2+ overload being mediated by reverse-mode mNCE activity and supporting ROS-induced ROS release as the primary trigger of ΔΨ m instability during reperfusion injury.","journal":"Journal of Biological Chemistry","year":2023,"id":331698,"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":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"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":475243,"name":"Kyriakos N. Papanicolaou","orcid":"0000-0003-3088-7119","position":1,"is_corresponding":false},{"id":641300,"name":"Agnieszka Sidor","orcid":null,"position":2,"is_corresponding":false},{"id":1057096,"name":"Michelle Y. Wang","orcid":"0000-0001-5084-5181","position":3,"is_corresponding":false},{"id":771356,"name":"Soroosh Solhjoo","orcid":"0000-0002-4908-2479","position":4,"is_corresponding":false},{"id":328212,"name":"Ting Liu","orcid":"0000-0002-8304-5751","position":5,"is_corresponding":false},{"id":270498,"name":"Brian O’Rourke","orcid":"0000-0002-5548-4853","position":6,"is_corresponding":false},{"id":328211,"name":"Deepthi Ashok","orcid":"0000-0003-0252-4716","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:09:25.015646Z","pmid":"37061004","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":[]}