{"doi":"10.1101/2022.11.01.514701","title":"Resting mitochondrial complex I from <i>Drosophila melanogaster</i> adopts a helix-locked state","abstract":"Abstract Respiratory complex I is a proton-pumping oxidoreductase key to bioenergetic metabolism. Biochemical studies have found a divide in the behavior of complex I in metazoans that aligns with the evolutionary split between Protostomia and Deuterostomia. Complex I from Deuterostomia including mammals can adopt an off-pathway “deactive” state, whereas complex I from Protostomia cannot. The presence of off-pathway states complicates the interpretation of structural results and has led to considerable mechanistic debate. Here we report the structure of mitochondrial complex I from the thoracic muscles of the model protostomian Drosophila melanogaster . We show that, although D. melanogaster complex I ( Dm -CI) does not deactivate the resting state of Dm -CI adopts multiple conformations. We identify a new helix-locked open state in which an N-terminal α-helix on the NDUFS4 subunit wedges between the peripheral and membrane arms. Comparison of the Dm -CI structure and conformational states to those observed in bacteria, yeast and mammals provides insight into the roles of subunits across organisms, explains why Dm -CI does not deactivate and reveals incompatibilities with current mechanistic models of complex I turnover. Additionally, the Dm -CI structure and novel regulatory mechanism will allow for the development of more selective pesticides for agriculture and human disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298430,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"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":470184,"name":"Anjaneyulu Murari","orcid":"0000-0002-7532-964X","position":1,"is_corresponding":false},{"id":470185,"name":"Shauna-Kay Rhooms","orcid":"0000-0002-1371-3208","position":2,"is_corresponding":false},{"id":291015,"name":"Edward Owusu-Ansah","orcid":"0000-0002-3451-1752","position":3,"is_corresponding":false},{"id":987480,"name":"James A. Letts","orcid":"0000-0002-9864-3586","position":4,"is_corresponding":false},{"id":987479,"name":"Abhilash Padavannil","orcid":"0000-0002-9949-6776","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T00:31:36.269611Z","pmid":null,"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":[]}