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While the roles of canonical translation regulators such as eIF2\u03b1 and 4E\u2010BP1 in exercise\u2010induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)\u2010induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress\u2010responsive translation factors, as eIF2\u03b1 phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA\u2010mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p\u2010mTOR, p\u20104EBP1, p\u2010S6K, p\u2010S6) and differentially modulated ubiquitin\u2010proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise\u2010induced adaptation to muscle wasting disorders.<\/jats:p>","DOI":"10.1096\/fj.202600161r","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:02:29Z","timestamp":1781103749000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in\u00a0Skeletal Muscle"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7341-8260","authenticated-orcid":false,"given":"Yingying","family":"Lin","sequence":"first","affiliation":[{"name":"Otolaryngology &amp; Head and Neck Center Zhejiang Provincial People's Hospital  Hangzhou 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