{"doi":"10.1101/2022.09.22.509020","title":"Yeast NDI1 expression prevents the unfolded protein response and reconfigures metabolism to restore neuronal function in mitochondrial complex I deficiency","abstract":"Abstract Mutations in mitochondrial complex I cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The mechanisms underlying complex I deficiency pathogenesis remain poorly understood, and as a result there are currently no available treatments. To better understand the causes of neuronal dysfunction in complex I deficiency, we modelled complex I deficiency in Drosophila by knocking down the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Remarkably, we find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1 in neurons, which couples NADH oxidation to transfer of electrons into the respiratory chain, reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Metabolomic analysis shows that NDI1 expression also reconfigures neuronal metabolism and implicates increased GABA levels as a contributor to the neurological manifestations of complex I deficiency. Together, these data indicate that NDI1 abrogates UPR signalling and reprogrammes metabolism to alleviate neuronal dysfunction caused by neuronal complex I deficiency.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":311561,"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":0,"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":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1007730,"name":"Daniel C. Ranson","orcid":"0000-0003-1166-5158","position":1,"is_corresponding":false},{"id":1008150,"name":"Emma L. Hamer","orcid":null,"position":2,"is_corresponding":false},{"id":616132,"name":"Ram Prosad Chakrabarty","orcid":"0000-0002-5425-6306","position":3,"is_corresponding":false},{"id":559559,"name":"Francesca Mattedi","orcid":"0000-0002-0306-5796","position":4,"is_corresponding":false},{"id":1007731,"name":"Laura Fort‐Aznar","orcid":"0000-0002-3869-7494","position":5,"is_corresponding":false},{"id":1007732,"name":"Frank Hirth","orcid":"0000-0001-8581-9450","position":6,"is_corresponding":false},{"id":378645,"name":"Sean T. Sweeney","orcid":"0000-0003-2673-9578","position":7,"is_corresponding":false},{"id":559561,"name":"Alessio Vagnoni","orcid":"0000-0003-2947-9193","position":8,"is_corresponding":false},{"id":104272,"name":"Navdeep S. Chandel","orcid":"0000-0001-7208-3886","position":9,"is_corresponding":false},{"id":371759,"name":"J.E. Bateman","orcid":"0000-0003-0754-1785","position":10,"is_corresponding":false},{"id":1007729,"name":"Lucy Granat","orcid":"0000-0002-2767-9880","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:33:28.480200Z","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":[]}