{"doi":"10.1101/2024.08.05.606704","title":"Mfn2 promotes NCLX-mediated Ca <sup>2+</sup> release from mitochondria","abstract":"Mfn2 is a mitochondrial outer membrane fusion protein with the additional role of tethering mitochondria to the ER. Here, we describe a novel connection between Mfn2 and calcium release from mitochondria. We show that Mfn2 controls the mitochondrial inner membrane sodium-calcium exchange protein NCLX, which is a major source for calcium release from mitochondria. This discovery was made with the fungal toxin Phomoxanthone (PXA), which induces calcium release from mitochondria. PXA-induced calcium release is blocked by a chemical inhibitor of NCLX, while NCLX and Mfn2 deletions both also prevent PXA-induced calcium release. CETSA experiments show that PXA directly targets Mfn2, which likely controls NCLX through physical interactions since co-immunoprecipitation and proximity ligation assays show increased association between Mfn2 and NCLX upon treatment with PXA. Interactions between Mfn2 and NCLX also increase when cells are treated with mitochondrial ROS-inducing conditions, such as oligomycin treatment of respiring cells, while the interactions do not increase in Oma1 -/- cells. It seems likely that opening of cristae by Oma1-mediated cleavage of Opa1 promotes translocation of NCLX from cristae to the rim where it can come into contact with Mfn2 thus promoting PXA-induced calcium release from mitochondria. These results therefore delineate a pathway that connects ROS produced inside mitochondria with calcium release and signaling in the cytosol.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":488809,"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":0.9599,"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":1333375,"name":"Akash Saha","orcid":"0000-0002-8205-0911","position":1,"is_corresponding":false},{"id":615299,"name":"Andrew W. Caliri","orcid":"0000-0003-3119-113X","position":2,"is_corresponding":false},{"id":325893,"name":"Essam A. Assali","orcid":"0000-0002-7788-7047","position":3,"is_corresponding":false},{"id":1333746,"name":"Alejandro Martorell Riera","orcid":null,"position":4,"is_corresponding":false},{"id":984546,"name":"Samuel Itskanov","orcid":"0000-0003-0705-2359","position":5,"is_corresponding":false},{"id":1225480,"name":"Sean Atamdede","orcid":null,"position":6,"is_corresponding":false},{"id":1333747,"name":"Catalina S. Magana","orcid":null,"position":7,"is_corresponding":false},{"id":1333376,"name":"Björn Stork","orcid":"0000-0002-4167-7806","position":8,"is_corresponding":false},{"id":242295,"name":"Orian S. Shirihai","orcid":"0000-0001-8466-3431","position":9,"is_corresponding":false},{"id":334828,"name":"Israel Sekler","orcid":"0000-0002-7550-1550","position":10,"is_corresponding":false},{"id":37858,"name":"Uri Manor","orcid":"0000-0002-9802-1955","position":11,"is_corresponding":false},{"id":994914,"name":"Carla M. Koehler","orcid":"0000-0001-8685-2412","position":12,"is_corresponding":false},{"id":323972,"name":"Alexander M. van der Bliek","orcid":"0000-0002-6211-5765","position":13,"is_corresponding":false},{"id":1333374,"name":"Panagiota Kolitsida","orcid":"0000-0002-7330-1766","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T02:08:19.655720Z","pmid":"39149365","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":[]}