{"doi":"10.1093/pnasnexus/pgaf178","title":"Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism","abstract":"Abstract The integrin effector, PTRH2, associates with mitochondria in adherent cells where its function has not been elucidated (Jan Y, et al. 2004. A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Cell. 116:751–762; Griffiths GS, et al. 2011. Bit-1 mediates integrin-dependent cell survival through activation of the NF{kappa}B pathway. J Biol Chem. 286:14713–14723). PTRH2 loss-of-function mutations cause multisystem disease in children through an unknown mechanism. We sought to determine the role of mitochondrial PTRH2. We used immunoprecipitation/mass spectrometric proteomics to identify PTRH2 interacting partners: TRABID (a deubiquitinase [DUB]) and respiratory complex I NADH: ubiquinone oxidoreductase core subunit 5 (mt-ND5). We show for the first time that mitochondrial PTRH2 regulates TRABID's ability to deubiquitylate mt-ND5. In cells lacking PTRH2 expression, mt-ND5 stability is significantly increased due to aberrant TRABID-mediated deubiquitylation of mt-ND5. This increase in mt-ND5 stability promotes complex I activity and ATP production, which under stress conditions leads to mitochondrial Ca2+ overload. Reexpression of mitochondrial PTRH2 blocks TRABID-mediated mt-ND5 deubiquitylation, resulting in mt-ND5 polyubiquitylation and proteasomal degradation. Inhibiting complex I or TRABID activity rescued PTRH2 loss-of-function mutant patient cells from mitochondrial Ca2+ overload under stress. Immunostaining analysis of ptrh2+/+ and ptrh2−/– mouse skeletal muscle revealed a negative relationship between PTRH2 and mt-ND5, confirming a regulatory role for PTRH2 in controlling mt-ND5 stability. Taken together, mitochondrial PTRH2 is a regulator of metabolic homeostasis that, when lost, promotes mitochondrial Ca2+ overload when cells are exposed to stress signals. Targeting mt-ND5 stability through PTRH2-mediated regulation of TRABID's DUB function provides a novel mechanistic approach to inhibit mitochondrial Ca2+ overload in diseases that occur due to dysregulated mitochondria.","journal":"PNAS Nexus","year":2025,"id":544523,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"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":630187,"name":"Femke J. Aan","orcid":"0009-0006-7885-6118","position":1,"is_corresponding":false},{"id":1268634,"name":"Natalija Glibetić","orcid":"0000-0001-8592-260X","position":2,"is_corresponding":false},{"id":630186,"name":"Daniela Ramaccini","orcid":"0000-0003-1160-7599","position":3,"is_corresponding":false},{"id":630188,"name":"Lorenzo Modesti","orcid":"0000-0001-8206-6625","position":4,"is_corresponding":false},{"id":1025811,"name":"Veronica Angela Maria Vitto","orcid":"0000-0002-7189-350X","position":5,"is_corresponding":false},{"id":631365,"name":"Vanessa Montoya‐Uribe","orcid":null,"position":6,"is_corresponding":false},{"id":505507,"name":"Austin Corpuz","orcid":null,"position":7,"is_corresponding":false},{"id":1081854,"name":"Sonia Missiroli","orcid":"0000-0003-4530-617X","position":8,"is_corresponding":false},{"id":1434662,"name":"Inês C. M. Simões","orcid":"0000-0002-9701-9431","position":9,"is_corresponding":false},{"id":630189,"name":"Yaiza Potes","orcid":"0000-0002-4687-6230","position":10,"is_corresponding":false},{"id":630190,"name":"Mariusz R. Wiȩckowski","orcid":"0000-0003-0789-4521","position":11,"is_corresponding":false},{"id":504459,"name":"Joe W. Ramos","orcid":"0000-0002-9708-2115","position":12,"is_corresponding":false},{"id":548760,"name":"Paolo Pinton","orcid":"0000-0001-7108-6508","position":13,"is_corresponding":false},{"id":504460,"name":"Michelle L. Matter","orcid":"0000-0002-5988-9663","position":14,"is_corresponding":false},{"id":630192,"name":"Carlotta Giorgi","orcid":"0000-0002-2494-7405","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:53:12.864581Z","pmid":"40496187","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":[]}