{"doi":"10.1016/j.jbc.2024.107403","title":"Upregulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain","abstract":"Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional up-regulated of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally down-regulated in cellular and murine models of mitochondrial defects. We identified a role for the post-transcriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca 2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo , using a model of mitochondria-associated disease in C. elegans , that normalization of lysosomal Ca 2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.","journal":"Journal of Biological Chemistry","year":2024,"id":446802,"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":0.953,"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":1263991,"name":"Leonardo Pereyra","orcid":"0000-0002-9139-9664","position":1,"is_corresponding":false},{"id":1263992,"name":"Justin Dale","orcid":"0009-0007-9433-857X","position":2,"is_corresponding":false},{"id":1263993,"name":"King Faisal Yambire","orcid":"0000-0003-2417-450X","position":3,"is_corresponding":false},{"id":890767,"name":"Silvia Maglioni","orcid":"0000-0001-5272-9264","position":4,"is_corresponding":false},{"id":371479,"name":"Alfonso Schiavi","orcid":"0000-0002-6563-8035","position":5,"is_corresponding":false},{"id":371480,"name":"Natascia Ventura","orcid":"0000-0001-8718-4321","position":6,"is_corresponding":false},{"id":1212209,"name":"Ira Milošević","orcid":"0000-0001-6440-3763","position":7,"is_corresponding":false},{"id":347300,"name":"Nuno Raimundo","orcid":"0000-0002-5988-9129","position":8,"is_corresponding":false},{"id":911544,"name":"Francesco Agostini","orcid":"0000-0002-9833-6498","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T02:01:54.980444Z","pmid":"38782205","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":[]}