{"doi":"10.1101/2020.08.12.248161","title":"UPR <sup>mt</sup> scales mitochondrial network expansion with protein synthesis via mitochondrial import","abstract":"Abstract As organisms develop, individual cells generate mitochondria to fulfill physiologic requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth and impacted by environmental cues. The mitochondrial unfolded protein response (UPR mt ) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS) 1 . Here, we demonstrate that ATFS-1 mediates an adaptable mitochondrial expansion program that is active throughout normal development. Developmental mitochondrial network expansion required the relatively inefficient MTS 2 in ATFS-1, which allowed the transcription factor to be responsive to parameters that impact protein import capacity of the entire mitochondrial network. Increasing the strength of the ATFS-1 MTS impaired UPR mt activity throughout development due to increased accumulation within mitochondria. The insulin-like signaling-TORC1 3 and AMPK pathways affected UPR mt activation 4,5 in a manner that correlated with protein synthesis. Manipulation to increase protein synthesis caused UPR mt activation. Alternatively, S6 kinase inhibition had the opposite effect due to increased mitochondrial accumulation of ATFS-1. However, ATFS-1 with a dysfunctional MTS 6 constitutively increased UPR mt activity independent of TORC1 function. Lastly, expression of a single protein with a strong MTS, was sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPR mt activation. Mitochondrial network expansion is attenuated once ATFS-1 can be imported.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":130700,"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":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":583949,"name":"Yunguang Du","orcid":null,"position":1,"is_corresponding":false},{"id":583950,"name":"Qiyun Yang","orcid":null,"position":2,"is_corresponding":false},{"id":583951,"name":"Andrew Melber","orcid":null,"position":3,"is_corresponding":false},{"id":583952,"name":"Nandhitha Uma Naresh","orcid":null,"position":4,"is_corresponding":false},{"id":583953,"name":"Joshua Lavelle","orcid":null,"position":5,"is_corresponding":false},{"id":306037,"name":"Pengpeng Liu","orcid":"0000-0002-4891-8780","position":6,"is_corresponding":false},{"id":583472,"name":"Hilla Weidberg","orcid":"0000-0001-7353-7536","position":7,"is_corresponding":false},{"id":246162,"name":"Rui Li","orcid":"0009-0009-8136-4159","position":8,"is_corresponding":false},{"id":476626,"name":"Jun Yu","orcid":"0000-0003-3109-4102","position":9,"is_corresponding":false},{"id":246163,"name":"Lihua Julie Zhu","orcid":"0000-0001-7416-0590","position":10,"is_corresponding":false},{"id":266318,"name":"Lara Strittmatter","orcid":"0000-0002-2042-6071","position":11,"is_corresponding":false},{"id":237112,"name":"Cole M. Haynes","orcid":"0000-0003-2110-5648","position":12,"is_corresponding":false},{"id":583471,"name":"Tomer Shpilka","orcid":"0000-0002-8339-9656","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:15:56.698770Z","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":[]}