{"doi":"10.1093/function/zqac001","title":"ATP Synthase K+- and H+-fluxes Drive ATP Synthesis and Enable Mitochondrial K+-“Uniporter” Function: II. Ion and ATP Synthase Flux Regulation","abstract":"Abstract We demonstrated that ATP synthase serves the functions of a primary mitochondrial K+ “uniporter,” i.e., the primary way for K+ to enter mitochondria. This K+ entry is proportional to ATP synthesis, regulating matrix volume and energy supply-vs-demand matching. We show that ATP synthase can be upregulated by endogenous survival-related proteins via IF1. We identified a conserved BH3-like domain of IF1 which overlaps its “minimal inhibitory domain” that binds to the β-subunit of F1. Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF1 and exert effects, requiring this interaction, comparable to diazoxide to augment ATP synthase's H+ and K+ flux and ATP synthesis. Bcl-xL and Mcl-1, but not Bcl-2, serve as endogenous regulatory ligands of ATP synthase via interaction with IF1 at this BH3-like domain, to increase its chemo-mechanical efficiency, enabling its function as the recruitable mitochondrial KATP-channel that can limit ischemia-reperfusion injury. Using Bayesian phylogenetic analysis to examine potential bacterial IF1-progenitors, we found that IF1 is likely an ancient (∼2 Gya) Bcl-family member that evolved from primordial bacteria resident in eukaryotes, corresponding to their putative emergence as symbiotic mitochondria, and functioning to prevent their parasitic ATP consumption inside the host cell.","journal":"Function","year":2022,"id":246475,"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":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":682049,"name":"Evgeny Kobrinsky","orcid":"0000-0001-6883-9900","position":1,"is_corresponding":false},{"id":471092,"name":"Dmitry B. Zorov","orcid":"0000-0003-0863-8490","position":2,"is_corresponding":false},{"id":682782,"name":"Hanne Nuss","orcid":null,"position":3,"is_corresponding":false},{"id":559078,"name":"Yael Yaniv","orcid":"0000-0002-5183-6284","position":4,"is_corresponding":false},{"id":291051,"name":"Kenneth W. Fishbein","orcid":"0000-0002-6353-4603","position":5,"is_corresponding":false},{"id":258549,"name":"Rafael de Cabo","orcid":"0000-0003-2830-5693","position":6,"is_corresponding":false},{"id":435565,"name":"Lluı́s Montoliu","orcid":"0000-0003-3941-1176","position":7,"is_corresponding":false},{"id":434249,"name":"Sandra B. Gabelli","orcid":"0000-0003-1205-5204","position":8,"is_corresponding":false},{"id":258544,"name":"Miguel A. Aon","orcid":"0000-0002-4355-5431","position":9,"is_corresponding":false},{"id":383578,"name":"Sonia Cortassa","orcid":"0000-0001-7224-9858","position":10,"is_corresponding":false},{"id":471093,"name":"Steven J. Sollott","orcid":"0000-0003-1730-2956","position":11,"is_corresponding":false},{"id":286635,"name":"Magdalena Juhaszova","orcid":"0000-0001-9571-9541","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T00:23:43.438539Z","pmid":"35187492","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":[]}