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Here, we studied mechanisms of copper deficiency using systems biology approaches to contrast isogenic CTR1- and COX17-deficient cells, which model copper deficiency at the level of the whole cell or complex IV, respectively. Multiomics approaches revealed distinct signaling mechanisms elicited by compartment-specific genetic defects of copper homeostasis, spanning multiple organelles and biological functions. Specifically, COX17 KO cells exhibited elevated AMPK activity and blunted mTOR activity relative to CTR1-null cells. Manipulating mTOR activity elicited inverse effects on survival in CTR1-deficient cells and flies as compared with their COX17-deficient counterparts. Increased mTOR activity and downstream protein synthesis are adaptive in models of copper deficiency but deleterious in COX17-deficient cells and flies. We propose that mTOR activation represents a resilience mechanism that fails following sustained copper deficiency and impairments to mitochondrial respiration.<\/jats:p>","DOI":"10.1091\/mbc.e26-01-0021","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:51:21Z","timestamp":1778691081000},"source":"Crossref","is-referenced-by-count":0,"title":["Distinct signaling mechanisms and proteome phenotypes are elicited by compartment-specific genetic defects of copper homeostasis"],"prefix":"10.1091","volume":"37","author":[{"given":"Alicia R.","family":"Lane","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta, GA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Biophysics, 307 Linus Pauling Science Center, Oregon State University, Corvallis, OR 97331"},{"name":"Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University, Corvallis, OR 97331"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avanti","family":"Gokhale","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta, GA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Zlatic","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta, GA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke M.","family":"Allen","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Illinois State University, Normal, IL 61761"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah E.","family":"Scher","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta, GA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University, Atlanta, Georgia, 30322"},{"name":"Department of Neurology, Emory University, Atlanta, Georgia, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duc M.","family":"Duong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emory University, Atlanta, Georgia, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blaine R.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University, Atlanta, Georgia, 30322"},{"name":"Department of Neurology, Emory University, Atlanta, Georgia, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alysia D.","family":"Vrailas-Mortimer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Biophysics, 307 Linus Pauling Science Center, Oregon State University, Corvallis, OR 97331"},{"name":"Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University, Corvallis, OR 97331"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta, GA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Faundez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta, GA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1076","reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12860"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03436-3"},{"key":"e_1_3_4_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00763-x"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"e_1_3_4_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)95956-9"},{"key":"e_1_3_4_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12154-008-0003-5"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac156"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.52.33191"},{"key":"e_1_3_4_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-010-0629-y"},{"key":"e_1_3_4_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.116318"},{"key":"e_1_3_4_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000265"},{"key":"e_1_3_4_13_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4847"},{"key":"e_1_3_4_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01579-12"},{"key":"e_1_3_4_15_1","first-page":"45","article-title":"Analysis of survival data under the proportional hazards model","volume":"43","author":"Breslow NE","year":"1975","unstructured":"Breslow NE (1975). 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