{"doi":"10.7554/elife.100541.1","title":"Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation","abstract":"Summary Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI – is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic, stress-independent activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic, stress-independent activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that stress-independent activation of these ISR kinases reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic, stress-independent activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.","journal":"eLife","year":2024,"id":489056,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"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":1326916,"name":"Samantha Oviedo","orcid":"0000-0002-0072-2287","position":1,"is_corresponding":false},{"id":1226535,"name":"Sophia Krasny","orcid":null,"position":2,"is_corresponding":false},{"id":1326917,"name":"Mashiat Zaman","orcid":"0000-0002-1385-6591","position":3,"is_corresponding":false},{"id":1252570,"name":"Rama Aldakhlallah","orcid":"0009-0008-5833-0244","position":4,"is_corresponding":false},{"id":857965,"name":"Prakhyat Mathur","orcid":"0000-0002-3129-4465","position":5,"is_corresponding":false},{"id":883443,"name":"Gerald Pfeffer","orcid":"0000-0002-7657-7098","position":6,"is_corresponding":false},{"id":310926,"name":"Michael J. Bollong","orcid":"0000-0001-9439-1476","position":7,"is_corresponding":false},{"id":586828,"name":"Timothy E. Shutt","orcid":"0000-0001-5299-2943","position":8,"is_corresponding":false},{"id":514884,"name":"Danielle A. Grotjahn","orcid":"0000-0001-5908-7882","position":9,"is_corresponding":false},{"id":141781,"name":"R. Luke Wiseman","orcid":"0000-0001-9287-6840","position":10,"is_corresponding":false},{"id":820856,"name":"Kelsey R Baron","orcid":"0000-0002-6275-7522","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T02:08:23.929823Z","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":[]}