{"doi":"10.1101/2023.06.25.546449","title":"A mitochondrial surveillance mechanism activated by <i>SRSF2</i> mutations in hematologic malignancies","abstract":"Abstract Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2 P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2 P95H -induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2 P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2 P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2 P95H mutant MDS and AML.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":399942,"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":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1148362,"name":"Sudhish A. Devadiga","orcid":"0009-0002-3252-3458","position":1,"is_corresponding":false},{"id":75037,"name":"Robert F. Stanley","orcid":"0000-0002-2308-6914","position":2,"is_corresponding":false},{"id":900380,"name":"Ryan Morrow","orcid":null,"position":3,"is_corresponding":false},{"id":282670,"name":"Kevin A. Janssen","orcid":"0000-0002-6980-9575","position":4,"is_corresponding":false},{"id":479388,"name":"Mathieu Quesnel-Vallières","orcid":"0000-0001-9945-8123","position":5,"is_corresponding":false},{"id":1176621,"name":"Oz Pomp","orcid":null,"position":6,"is_corresponding":false},{"id":1176272,"name":"Adam A. Moverley","orcid":"0009-0007-1816-3317","position":7,"is_corresponding":false},{"id":1046169,"name":"Chenchen Li","orcid":"0000-0002-5888-414X","position":8,"is_corresponding":false},{"id":633414,"name":"Nicolas Skuli","orcid":null,"position":9,"is_corresponding":false},{"id":318325,"name":"Martin Carroll","orcid":"0000-0002-5622-3735","position":10,"is_corresponding":false},{"id":489812,"name":"Jian Huang","orcid":"0000-0002-1649-0038","position":11,"is_corresponding":false},{"id":227783,"name":"Douglas C. Wallace","orcid":"0000-0002-7480-8278","position":12,"is_corresponding":false},{"id":302511,"name":"Kristen W. Lynch","orcid":"0000-0002-0120-8079","position":13,"is_corresponding":false},{"id":75043,"name":"Omar Abdel-Wahab","orcid":"0000-0002-3907-6171","position":14,"is_corresponding":false},{"id":321415,"name":"Peter S. Klein","orcid":"0000-0002-2011-8538","position":15,"is_corresponding":false},{"id":636884,"name":"Xiaolei Liu","orcid":"0000-0003-3771-4165","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T01:20:00.023537Z","pmid":"38712254","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":[]}