{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:02:30Z","timestamp":1785214950892,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,22]]},"group-title":"Genetics","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Gift from Dave and Pat Holveck"},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R35-GM134863"],"award-info":[{"award-number":["R35-GM134863"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Primary mitochondrial diseases (PMD) have limited disease-modifying therapies, currently applicable to only 3 of over 400 discrete gene disorders. Cycloheximide (CHX) is a global cytosolic translation inhibitor we previously reported to rescue PMD preclinical models, although its toxicity precluded clinical development. To identify specific mediators underlying CHX treatment benefit in PMD, SOMAscan-based proteomics was performed in complex I deficient and genetic disease fibroblast cell line models grown in galactose. Thrombopoietin (THPO) and insulin-like growth factor binding protein 5 (IGFBP5) were the only two differentially regulated proteins, together with ERK\/MAPK pathway dysregulation, identified upon CHX treatment in PMD versus healthy control cells. THPO inhibition by siRNA or pharmacologic approaches rescued stress-induced viability loss in patient fibroblasts having diverse PMD gene etiologies, and significantly improved mitochondrial stress, linear growth, and neuromuscular function in a classical\n                  <jats:italic>\n                    ndufs2\n                    <jats:sup>-\/-<\/jats:sup>\n                    C. elegans\n                  <\/jats:italic>\n                  model. IGFBP5 overexpression by lentiviral or mRNA approaches rescued cell viability across distinct PMD gene etiologies, as did IGF1 pharmacologic inhibition across both PMD mutant and\n                  <jats:italic>C. elegans<\/jats:italic>\n                  models. MAPK pharmacologic inhibition rescued multiple distinct complex I disease cells\u2019 survival, as well as mitochondrial stress in\n                  <jats:italic>\n                    SLC25A46\n                    <jats:sup>-\/-<\/jats:sup>\n                    C. elegans\n                  <\/jats:italic>\n                  . Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and\n                  <jats:italic>C. elegans<\/jats:italic>\n                  models. Additionally, single or combined pharmacologic inhibition of THPO or IGF1 significantly enhanced primary and metastatic osteosarcoma cell death. Collectively, targeted small molecule and genetic modulation of THPO, IGF1, or MAPK recapitulated the significant therapeutic benefit of CHX in PMD, while avoiding global translation inhibition. These novel PMD therapies likely confer benefit by attenuating MAPK-driven autophagy and potentially promoting noncanonical glucose uptake, improving cellular energy balance. Overall, these glucose signaling cellular pathway targets hold broad therapeutic promise for PMD patients, warranting further clinical research development.\n                <\/jats:p>","DOI":"10.64898\/2026.07.20.739625","type":"posted-content","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T15:25:19Z","timestamp":1784906719000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeted modulation of IGFBP5\/IGF1, THPO, and P38 MAPK signaling are potent therapeutic strategies generalizable for mitochondrial respiratory chain disease and osteosarcoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7451-5117","authenticated-orcid":false,"given":"Kelsey","family":"Keith","sequence":"first","affiliation":[{"name":"Department of Biomedical and Health Informatics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Peng","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1062-3071","authenticated-orcid":false,"given":"Cristina","family":"Remes","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Miranda","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Wachowski","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melis","family":"Kose","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrikant","family":"Dharaskar","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia, Philadelphia, 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