{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:41:43Z","timestamp":1789753303690,"version":"4.0.1"},"reference-count":92,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EXC 2030 - 390661388"],"award-info":[{"award-number":["EXC 2030 - 390661388"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB 1218 - 269925409"],"award-info":[{"award-number":["SFB 1218 - 269925409"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB 1678 - 520471345"],"award-info":[{"award-number":["SFB 1678 - 520471345"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SPP 2453 - 541742459"],"award-info":[{"award-number":["SPP 2453 - 541742459"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RU 5762 - 531902955"],"award-info":[{"award-number":["RU 5762 - 531902955"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005156","name":"Alexander von Humboldt-Stiftung","doi-asserted-by":"publisher","award":["Postdoctoral fellowship"],"award-info":[{"award-number":["Postdoctoral fellowship"]}],"id":[{"id":"10.13039\/100005156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Cell Biol"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in\n                    <jats:italic>Caenorhabditis<\/jats:italic>\n                    <jats:italic>elegans<\/jats:italic>\n                    and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine\u2013GCN2\u2013SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41556-025-01799-3","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T10:04:35Z","timestamp":1761905075000},"page":"1889-1901","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8032-9110","authenticated-orcid":false,"given":"Qiaochu","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4895-9459","authenticated-orcid":false,"given":"Konstantin","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuateima","family":"Niwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Riemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4734-9352","authenticated-orcid":false,"given":"Thorsten","family":"Hoppe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"1799_CR1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.51065","volume":"9","author":"MB Metzger","year":"2020","unstructured":"Metzger, M. B., Scales, J. L., Dunklebarger, M. F., Loncarek, J. & Weissman, A. M. A protein quality control pathway at the mitochondrial outer membrane. eLife 9, e51065 (2020).","journal-title":"eLife"},{"key":"1799_CR2","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.molcel.2010.10.021","volume":"40","author":"J-M Heo","year":"2010","unstructured":"Heo, J.-M. et al. A stress-responsive system for mitochondrial protein degradation. Mol. Cell 40, 465\u2013480 (2010).","journal-title":"Mol. Cell"},{"key":"1799_CR3","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1083\/jcb.201510098","volume":"213","author":"X Wu","year":"2016","unstructured":"Wu, X., Li, L. & Jiang, H. Doa1 targets ubiquitinated substrates for mitochondria-associated degradation. J. Cell Biol. 213, 49\u201363 (2016).","journal-title":"J. Cell Biol."},{"key":"1799_CR4","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1042\/BST0391509","volume":"39","author":"EB Taylor","year":"2011","unstructured":"Taylor, E. B. & Rutter, J. Mitochondrial quality control by the ubiquitin\u2013proteasome system. Biochem. Soc. Trans. 39, 1509\u20131513 (2011).","journal-title":"Biochem. Soc. Trans."},{"key":"1799_CR5","doi-asserted-by":"crossref","first-page":"270","DOI":"10.3389\/fcell.2020.00270","volume":"8","author":"S Ravanelli","year":"2020","unstructured":"Ravanelli, S., den Brave, F. & Hoppe, T. Mitochondrial quality control governed by ubiquitin. Front. Cell Dev. Biol. 8, 270 (2020).","journal-title":"Front. Cell Dev. Biol."},{"key":"1799_CR6","doi-asserted-by":"publisher","unstructured":"R\u00f6dl, S. & Herrmann, J. M. The role of the proteasome in mitochondrial protein quality control. IUBMB Life https:\/\/doi.org\/10.1002\/iub.2734 (2023).","DOI":"10.1002\/iub.2734"},{"key":"1799_CR7","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41586-019-1227-y","volume":"569","author":"CU M\u00e5rtensson","year":"2019","unstructured":"M\u00e5rtensson, C. U. et al. Mitochondrial protein translocation-associated degradation. Nature 569, 679\u2013683 (2019).","journal-title":"Nature"},{"key":"1799_CR8","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/s41556-021-00798-4","volume":"23","author":"T K\u00f6nig","year":"2021","unstructured":"K\u00f6nig, T. et al. MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. Nat. Cell Biol. 23, 1271\u20131286 (2021).","journal-title":"Nat. Cell Biol."},{"key":"1799_CR9","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.cub.2007.12.038","volume":"18","author":"M Neuspiel","year":"2008","unstructured":"Neuspiel, M. et al. Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr. Biol. 18, 102\u2013108 (2008).","journal-title":"Curr. Biol."},{"key":"1799_CR10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cub.2011.11.057","volume":"22","author":"V Soubannier","year":"2012","unstructured":"Soubannier, V. et al. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 22, 135\u2013141 (2012).","journal-title":"Curr. Biol."},{"key":"1799_CR11","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.13943","volume":"5","author":"AL Hughes","year":"2016","unstructured":"Hughes, A. L., Hughes, C. E., Henderson, K. A., Yazvenko, N. & Gottschling, D. E. Selective sorting and destruction of mitochondrial membrane proteins in aged yeast. eLife 5, e13943 (2016).","journal-title":"eLife"},{"key":"1799_CR12","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1016\/j.molcel.2021.08.021","volume":"81","author":"M-H Schuler","year":"2021","unstructured":"Schuler, M.-H. et al. Mitochondrial-derived compartments facilitate cellular adaptation to amino acid stress. Mol. Cell 81, 3786\u20133802.e13 (2021).","journal-title":"Mol. Cell"},{"key":"1799_CR13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.4161\/auto.2229","volume":"2","author":"S Rodriguez-Enriquez","year":"2006","unstructured":"Rodriguez-Enriquez, S., Kim, I., Currin, R. T. & Lemasters, J. J. Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2, 39\u201346 (2006).","journal-title":"Autophagy"},{"key":"1799_CR14","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.abb.2007.03.034","volume":"462","author":"I Kim","year":"2007","unstructured":"Kim, I., Rodriguez-Enriquez, S. & Lemasters, J. J. Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462, 245\u2013253 (2007).","journal-title":"Arch. Biochem. Biophys."},{"key":"1799_CR15","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1016\/j.celrep.2017.06.014","volume":"19","author":"M Morgenstern","year":"2017","unstructured":"Morgenstern, M. et al. Definition of a high-confidence mitochondrial proteome at quantitative scale. Cell Rep. 19, 2836\u20132852 (2017).","journal-title":"Cell Rep."},{"key":"1799_CR16","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1146\/annurev.biochem.76.052705.163409","volume":"76","author":"W Neupert","year":"2007","unstructured":"Neupert, W. & Herrmann, J. M. Translocation of proteins into mitochondria. Annu. Rev. Biochem. 76, 723\u2013749 (2007).","journal-title":"Annu. Rev. Biochem."},{"key":"1799_CR17","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nrm2959","volume":"11","author":"O Schmidt","year":"2010","unstructured":"Schmidt, O., Pfanner, N. & Meisinger, C. Mitochondrial protein import: from proteomics to functional mechanisms. Nat. Rev. Mol. Cell Biol. 11, 655\u2013667 (2010).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"1799_CR18","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1083\/jcb.201706043","volume":"216","author":"V Kr\u00fcger","year":"2017","unstructured":"Kr\u00fcger, V. et al. Identification of new channels by systematic analysis of the mitochondrial outer membrane. J. Cell Biol. 216, 3485\u20133495 (2017).","journal-title":"J. Cell Biol."},{"key":"1799_CR19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1042\/bse0470037","volume":"47","author":"F Palmieri","year":"2010","unstructured":"Palmieri, F. & Pierri, C. L. Mitochondrial metabolite transport. Essays Biochem. 47, 37\u201352 (2010).","journal-title":"Essays Biochem."},{"key":"1799_CR20","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.bbamem.2011.12.026","volume":"1818","author":"M Colombini","year":"2012","unstructured":"Colombini, M. VDAC structure, selectivity, and dynamics. Biochim. Biophys. Acta 1818, 1457\u20131465 (2012).","journal-title":"Biochim. Biophys. Acta"},{"key":"1799_CR21","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1126\/science.1219855","volume":"337","author":"RJ Youle","year":"2012","unstructured":"Youle, R. J. & van der Bliek, A. M. Mitochondrial fission, fusion, and stress. Science 337, 1062\u20131065 (2012).","journal-title":"Science"},{"key":"1799_CR22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41420-023-01353-w","volume":"9","author":"Y Zhang","year":"2023","unstructured":"Zhang, Y. et al. Synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles. Cell Death Discov. 9, 51 (2023).","journal-title":"Cell Death Discov."},{"key":"1799_CR23","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41580-020-00300-2","volume":"22","author":"J Song","year":"2021","unstructured":"Song, J., Herrmann, J. M. & Becker, T. Quality control of the mitochondrial proteome. Nat. Rev. Mol. Cell Biol. 22, 54\u201370 (2021).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"1799_CR24","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1242\/jcs.079293","volume":"124","author":"MM Cohen","year":"2011","unstructured":"Cohen, M. M. et al. Sequential requirements for the GTPase domain of the mitofusin Fzo1 and the ubiquitin ligase SCFMdm30 in mitochondrial outer membrane fusion. J. Cell Sci. 124, 1403\u20131410 (2011).","journal-title":"J. Cell Sci."},{"key":"1799_CR25","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.molcel.2012.05.041","volume":"47","author":"GP Leboucher","year":"2012","unstructured":"Leboucher, G. P. et al. Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol. Cell 47, 547\u2013557 (2012).","journal-title":"Mol. Cell"},{"key":"1799_CR26","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1091\/mbc.e08-02-0227","volume":"19","author":"MMJ Cohen","year":"2008","unstructured":"Cohen, M. M. J., Leboucher, G. P., Livnat-Levanon, N., Glickman, M. H. & Weissman, A. M. Ubiquitin\u2013proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion. Mol. Biol. Cell 19, 2457\u20132464 (2008).","journal-title":"Mol. Biol. Cell"},{"key":"1799_CR27","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1080\/15548627.2016.1252889","volume":"13","author":"N Belgareh-Touz\u00e9","year":"2017","unstructured":"Belgareh-Touz\u00e9, N., Cavellini, L. & Cohen, M. M. Ubiquitination of ERMES components by the E3 ligase Rsp5 is involved in mitophagy. Autophagy 13, 114\u2013132 (2017).","journal-title":"Autophagy"},{"key":"1799_CR28","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1091\/mbc.e02-12-0831","volume":"14","author":"S Fritz","year":"2003","unstructured":"Fritz, S., Weinbach, N. & Westermann, B. Mdm30 is an F-box protein required for maintenance of fusion-competent mitochondria in yeast. Mol. Biol. Cell 14, 2303\u20132313 (2003).","journal-title":"Mol. Biol. Cell"},{"key":"1799_CR29","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1111\/j.1365-2443.2008.01228.x","volume":"13","author":"K Ota","year":"2008","unstructured":"Ota, K., Kito, K., Okada, S. & Ito, T. A proteomic screen reveals the mitochondrial outer membrane protein Mdm34p as an essential target of the F-box protein Mdm30p. Genes Cells 13, 1075\u20131085 (2008).","journal-title":"Genes Cells"},{"key":"1799_CR30","doi-asserted-by":"crossref","first-page":"495","DOI":"10.15252\/embr.201643309","volume":"18","author":"Z Chen","year":"2017","unstructured":"Chen, Z. et al. Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy. EMBO Rep. 18, 495\u2013509 (2017).","journal-title":"EMBO Rep."},{"key":"1799_CR31","doi-asserted-by":"crossref","first-page":"e113033","DOI":"10.15252\/embj.2022113033","volume":"42","author":"Y Cao","year":"2023","unstructured":"Cao, Y. et al. A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease. EMBO J. 42, e113033 (2023).","journal-title":"EMBO J."},{"key":"1799_CR32","doi-asserted-by":"crossref","first-page":"17442","DOI":"10.1074\/jbc.270.29.17442","volume":"270","author":"ES Johnson","year":"1995","unstructured":"Johnson, E. S., Ma, P. C. M., Ota, I. M. & Varshavsky, A. A proteolytic pathway that recognizes ubiquitin as a degradation signal. J. Biol. Chem. 270, 17442\u201317456 (1995).","journal-title":"J. Biol. Chem."},{"key":"1799_CR33","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1534\/genetics.111.126797","volume":"187","author":"A Segref","year":"2011","unstructured":"Segref, A., Torres, S. & Hoppe, T. A screenable in vivo assay to study proteostasis networks in Caenorhabditis elegans. Genetics 187, 1235\u20131240 (2011).","journal-title":"Genetics"},{"key":"1799_CR34","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/s41556-017-0023-x","volume":"20","author":"A Ahier","year":"2018","unstructured":"Ahier, A. et al. Affinity purification of cell-specific mitochondria from whole animals resolves patterns of genetic mosaicism. Nat. Cell Biol. 20, 352\u2013360 (2018).","journal-title":"Nat. Cell Biol."},{"key":"1799_CR35","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1016\/j.jmb.2015.11.015","volume":"428","author":"D Barthelme","year":"2016","unstructured":"Barthelme, D. & Sauer, R. T. Origin and functional evolution of the Cdc48\/p97\/VCP AAA+ protein unfolding and remodeling machine. J. Mol. Biol. 428, 1861\u20131869 (2016).","journal-title":"J. Mol. Biol."},{"key":"1799_CR36","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.molcel.2017.10.028","volume":"69","author":"J van den Boom","year":"2018","unstructured":"van den Boom, J. & Meyer, H. VCP\/p97-mediated unfolding as a principle in protein homeostasis and signaling. Mol. Cell 69, 182\u2013194 (2018).","journal-title":"Mol. Cell"},{"key":"1799_CR37","first-page":"gkaa1011","volume":"49","author":"S Rath","year":"2020","unstructured":"Rath, S. et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 49, gkaa1011 (2020).","journal-title":"Nucleic Acids Res."},{"key":"1799_CR38","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.mam.2012.05.005","volume":"34","author":"F Palmieri","year":"2013","unstructured":"Palmieri, F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol. Aspects Med. 34, 465\u2013484 (2013).","journal-title":"Mol. Aspects Med."},{"key":"1799_CR39","volume":"10","author":"DG Ryan","year":"2021","unstructured":"Ryan, D. G. et al. Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism. eLife 10, e72593 (2021).","journal-title":"eLife"},{"key":"1799_CR40","doi-asserted-by":"crossref","first-page":"30409","DOI":"10.1074\/jbc.R200006200","volume":"277","author":"OE Owen","year":"2002","unstructured":"Owen, O. E., Kalhan, S. C. & Hanson, R. W. The key role of anaplerosis and cataplerosis for citric acid cycle function. J. Biol. Chem. 277, 30409\u201330412 (2002).","journal-title":"J. Biol. Chem."},{"key":"1799_CR41","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-13668-3","volume":"11","author":"I Mart\u00ednez-Reyes","year":"2020","unstructured":"Mart\u00ednez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020).","journal-title":"Nat. Commun."},{"key":"1799_CR42","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/ncb3233","volume":"17","author":"S Cardaci","year":"2015","unstructured":"Cardaci, S. et al. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat. Cell Biol. 17, 1317\u20131326 (2015).","journal-title":"Nat. Cell Biol."},{"key":"1799_CR43","doi-asserted-by":"crossref","first-page":"102838","DOI":"10.1016\/j.jbc.2022.102838","volume":"299","author":"PK Arnold","year":"2023","unstructured":"Arnold, P. K. & Finley, L. W. S. Regulation and function of the mammalian tricarboxylic acid cycle. J. Biol. Chem. 299, 102838 (2023).","journal-title":"J. Biol. Chem."},{"key":"1799_CR44","doi-asserted-by":"crossref","DOI":"10.1093\/genetics\/iyab089","volume":"219","author":"MD Walker","year":"2021","unstructured":"Walker, M. D. et al. WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization. Genetics 219, iyab089 (2021).","journal-title":"Genetics"},{"key":"1799_CR45","doi-asserted-by":"crossref","first-page":"26144","DOI":"10.1074\/jbc.M603636200","volume":"281","author":"J-H Kim","year":"2006","unstructured":"Kim, J.-H. & Johnston, M. Two glucose-sensing pathways converge on Rgt1 to regulate expression of glucose transporter genes in Saccharomyces cerevisiae. J. Biol. Chem. 281, 26144\u201326149 (2006).","journal-title":"J. Biol. Chem."},{"key":"1799_CR46","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1046\/j.1365-2958.1999.01413.x","volume":"32","author":"L Kraakman","year":"1999","unstructured":"Kraakman, L. et al. A Saccharomyces cerevisiae G-protein coupled receptor, Gpr1, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose. Mol. Microbiol. 32, 1002\u20131012 (1999).","journal-title":"Mol. Microbiol."},{"key":"1799_CR47","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1093\/emboj\/19.8.1887","volume":"19","author":"M Garcia-Barrio","year":"2000","unstructured":"Garcia-Barrio, M., Dong, J., Ufano, S. & Hinnebusch, A. G. Association of GCN1\u2013GCN20 regulatory complex with the N-terminus of eIF2\u03b1 kinase GCN2 is required for GCN2 activation. EMBO J. 19, 1887\u20131899 (2000).","journal-title":"EMBO J."},{"key":"1799_CR48","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S1097-2765(00)00028-9","volume":"6","author":"J Dong","year":"2000","unstructured":"Dong, J., Qiu, H., Garcia-Barrio, M., Anderson, J. & Hinnebusch, A. G. Uncharged tRNA Activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol. Cell 6, 269\u2013279 (2000).","journal-title":"Mol. Cell"},{"key":"1799_CR49","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1093\/emboj\/20.6.1425","volume":"20","author":"H Qiu","year":"2001","unstructured":"Qiu, H., Dong, J., Hu, C., Francklyn, C. S. & Hinnebusch, A. G. The tRNA-binding moiety in GCN2 contains a dimerization domain that interacts with the kinase domain and is required for tRNA binding and kinase activation. EMBO J. 20, 1425\u20131438 (2001).","journal-title":"EMBO J."},{"key":"1799_CR50","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2022.102629","volume":"298","author":"JB Br\u00fcggenthies","year":"2022","unstructured":"Br\u00fcggenthies, J. B. et al. A cell-based chemical-genetic screen for amino acid stress response inhibitors reveals torins reverse stress kinase GCN2 signaling. J. Biol. Chem. 298, 102629 (2022).","journal-title":"J. Biol. Chem."},{"key":"1799_CR51","doi-asserted-by":"crossref","first-page":"E1329","DOI":"10.1152\/ajpendo.00525.2011","volume":"302","author":"KM Dodd","year":"2012","unstructured":"Dodd, K. M. & Tee, A. R. Leucine and mTORC1: a complex relationship. Am. J. Physiol. Endocrinol. Metab. 302, E1329\u2013E1342 (2012).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"1799_CR52","doi-asserted-by":"publisher","unstructured":"Ravanelli, S. et al. Reprograming of proteasomal degradation by branched chain amino acid metabolism. Aging Cell https:\/\/doi.org\/10.1111\/acel.13725 (2022).","DOI":"10.1111\/acel.13725"},{"key":"1799_CR53","doi-asserted-by":"publisher","unstructured":"Lesnik, C. et al. Enhanced branched-chain amino acid metabolism improves age-related reproduction in C. elegans. Nat. Metab. https:\/\/doi.org\/10.1038\/s42255-024-00996-y (2024).","DOI":"10.1038\/s42255-024-00996-y"},{"key":"1799_CR54","doi-asserted-by":"crossref","DOI":"10.15252\/embr.202256100","volume":"24","author":"V Stonyte","year":"2023","unstructured":"Stonyte, V. et al. The GCN2\/eIF2\u03b1K stress kinase regulates PP1 to ensure mitotic fidelity. EMBO Rep. 24, e56100 (2023).","journal-title":"EMBO Rep."},{"key":"1799_CR55","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.tcb.2016.12.002","volume":"27","author":"L Qi","year":"2017","unstructured":"Qi, L., Tsai, B. & Arvan, P. New insights into the physiological role of endoplasmic reticulum-associated degradation. Trends Cell Biol. 27, 430\u2013440 (2017).","journal-title":"Trends Cell Biol."},{"key":"1799_CR56","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1111\/j.1365-2443.2007.01108.x","volume":"12","author":"Y Sasagawa","year":"2007","unstructured":"Sasagawa, Y., Yamanaka, K. & Ogura, T. ER E3 ubiquitin ligase HRD-1 and its specific partner chaperone BiP play important roles in ERAD and developmental growth in Caenorhabditis elegans. Genes Cells 12, 1063\u20131073 (2007).","journal-title":"Genes Cells"},{"key":"1799_CR57","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1038\/s41556-022-01025-4","volume":"24","author":"S Efstathiou","year":"2022","unstructured":"Efstathiou, S. et al. ER-associated RNA silencing promotes ER quality control. Nat. Cell Biol. 24, 1714\u20131725 (2022).","journal-title":"Nat. Cell Biol."},{"key":"1799_CR58","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1042\/bj1280461","volume":"128","author":"S Chakrabarti","year":"1972","unstructured":"Chakrabarti, S., Dube, D. K. & Roy, S. C. Effects of emetine and cycloheximide on mitochondrial protein synthesis in different systems. Biochem. J. 128, 461\u2013462 (1972).","journal-title":"Biochem. J."},{"key":"1799_CR59","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1016\/S0021-9258(18)53941-7","volume":"268","author":"M Fujiki","year":"1993","unstructured":"Fujiki, M. & Verner, K. Coupling of cytosolic protein synthesis and mitochondrial protein import in yeast. Evidence for cotranslational import in vivo. J. Biol. Chem. 268, 1914\u20131920 (1993).","journal-title":"J. Biol. Chem."},{"key":"1799_CR60","doi-asserted-by":"crossref","first-page":"3663","DOI":"10.1242\/jcs.052415","volume":"122","author":"Y Sasagawa","year":"2009","unstructured":"Sasagawa, Y. et al. Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner. J. Cell Sci. 122, 3663\u20133672 (2009).","journal-title":"J. Cell Sci."},{"key":"1799_CR61","doi-asserted-by":"crossref","first-page":"14406","DOI":"10.1073\/pnas.1408401111","volume":"111","author":"N Miyata","year":"2014","unstructured":"Miyata, N. et al. Pharmacologic rescue of an enzyme-trafficking defect in primary hyperoxaluria 1. Proc. Natl Acad. Sci. USA 111, 14406\u201314411 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1799_CR62","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-28272-1","volume":"13","author":"E Lionaki","year":"2022","unstructured":"Lionaki, E. et al. Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis. Nat. Commun. 13, 651 (2022).","journal-title":"Nat. Commun."},{"key":"1799_CR63","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s10545-015-9814-z","volume":"38","author":"XL Wang","year":"2015","unstructured":"Wang, X. L., Li, C. J., Xing, Y., Yang, Y. H. & Jia, J. P. Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J. Inherit. Metab. Dis. 38, 855\u2013861 (2015).","journal-title":"J. Inherit. Metab. Dis."},{"key":"1799_CR64","doi-asserted-by":"crossref","first-page":"1220638","DOI":"10.3389\/fonc.2023.1220638","volume":"13","author":"E Xu","year":"2023","unstructured":"Xu, E., Ji, B., Jin, K. & Chen, Y. Branched-chain amino acids catabolism and cancer progression: focus on therapeutic interventions. Front. Oncol. 13, 1220638 (2023).","journal-title":"Front. Oncol."},{"key":"1799_CR65","doi-asserted-by":"publisher","unstructured":"Kalita, B. et al. PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma. Cell https:\/\/doi.org\/10.1016\/j.cell.2025.03.008 (2025).","DOI":"10.1016\/j.cell.2025.03.008"},{"key":"1799_CR66","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2022.111198","volume":"40","author":"MO Abdullah","year":"2022","unstructured":"Abdullah, M. O. et al. Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids. Cell Rep. 40, 111198 (2022).","journal-title":"Cell Rep."},{"key":"1799_CR67","doi-asserted-by":"crossref","first-page":"239750","DOI":"10.1155\/2014\/239750","volume":"2014","author":"C Liang","year":"2014","unstructured":"Liang, C., Curry, B. J., Brown, P. L. & Zemel, M. B. Leucine modulates mitochondrial biogenesis and SIRT1-AMPK signaling in C2C12 myotubes. J. Nutr. Metab. 2014, 239750 (2014).","journal-title":"J. Nutr. Metab."},{"key":"1799_CR68","volume":"15","author":"X Wei","year":"2024","unstructured":"Wei, X. et al. Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis. Nat. Commun. 15, 659 (2024).","journal-title":"Nat. Commun."},{"key":"1799_CR69","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1126\/science.aay2494","volume":"368","author":"Z Zhou","year":"2020","unstructured":"Zhou, Z. et al. Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes. Science 368, 54\u201360 (2020).","journal-title":"Science"},{"key":"1799_CR70","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/bs.mie.2024.09.001","volume":"707","author":"P-C Liao","year":"2024","unstructured":"Liao, P.-C. & Pon, L. A. Analysis of the mitochondria-associated degradation pathway (MAD) in yeast cells. Methods Enzymol. 707, 585\u2013610 (2024).","journal-title":"Methods Enzymol."},{"key":"1799_CR71","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.tibs.2011.06.001","volume":"36","author":"A Stolz","year":"2011","unstructured":"Stolz, A., Hilt, W., Buchberger, A. & Wolf, D. H. Cdc48: a power machine in protein degradation. Trends Biochem. Sci. 36, 515\u2013523 (2011).","journal-title":"Trends Biochem. Sci."},{"key":"1799_CR72","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.ceb.2011.05.007","volume":"23","author":"M Karbowski","year":"2011","unstructured":"Karbowski, M. & Youle, R. J. Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Curr. Opin. Cell Biol. 23, 476\u2013482 (2011).","journal-title":"Curr. Opin. Cell Biol."},{"key":"1799_CR73","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","volume":"77","author":"S Brenner","year":"1974","unstructured":"Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71\u201394 (1974).","journal-title":"Genetics"},{"key":"1799_CR74","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-33467-7","volume":"13","author":"A Segref","year":"2022","unstructured":"Segref, A. et al. Thermosensation in Caenorhabditis elegans is linked to ubiquitin-dependent protein turnover via insulin and calcineurin signalling. Nat. Commun. 13, 5874 (2022).","journal-title":"Nat. Commun."},{"key":"1799_CR75","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature01278","volume":"421","author":"RS Kamath","year":"2003","unstructured":"Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231\u2013237 (2003).","journal-title":"Nature"},{"key":"1799_CR76","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1101\/gr.2505604","volume":"14","author":"J-F Rual","year":"2004","unstructured":"Rual, J.-F. et al. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 14, 2162\u20132168 (2004).","journal-title":"Genome Res."},{"key":"1799_CR77","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/s41596-018-0082-x","volume":"14","author":"CS Hughes","year":"2019","unstructured":"Hughes, C. S. et al. Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. Nat. Protoc. 14, 68\u201385 (2019).","journal-title":"Nat. Protoc."},{"key":"1799_CR78","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nature11315","volume":"489","author":"D Vilchez","year":"2012","unstructured":"Vilchez, D. et al. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489, 263\u2013268 (2012).","journal-title":"Nature"},{"key":"1799_CR79","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0091-679X(06)80001-4","volume":"80","author":"F Pallotti","year":"2007","unstructured":"Pallotti, F. & Lenaz, G. Isolation and subfractionation of mitochondria from animal cells and tissue culture lines. Methods Cell. Biol. 80, 3\u201344 (2007).","journal-title":"Methods Cell. Biol."},{"key":"1799_CR80","doi-asserted-by":"crossref","first-page":"e349","DOI":"10.7717\/peerj.349","volume":"2","author":"N Nishimura","year":"2014","unstructured":"Nishimura, N., Gotoh, T., Oike, Y. & Yano, M. TMEM65 is a mitochondrial inner-membrane protein. PeerJ 2, e349 (2014).","journal-title":"PeerJ"},{"key":"1799_CR81","doi-asserted-by":"crossref","first-page":"102085","DOI":"10.1016\/j.jbc.2022.102085","volume":"298","author":"F Fischer","year":"2022","unstructured":"Fischer, F. et al. Ingestion of single guide RNAs induces gene overexpression and extends lifespan in Caenorhabditis elegans via CRISPR activation. J. Biol. Chem. 298, 102085 (2022).","journal-title":"J. Biol. Chem."},{"key":"1799_CR82","doi-asserted-by":"crossref","first-page":"e4057","DOI":"10.21769\/BioProtoc.4057","volume":"11","author":"L Murschall","year":"2021","unstructured":"Murschall, L., Peker, E., MacVicar, T., Langer, T. & Riemer, J. Protein import assay into mitochondria isolated from human cells. Bio Protoc. 11, e4057 (2021).","journal-title":"Bio Protoc."},{"key":"1799_CR83","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-15346-1","volume":"11","author":"BC Searle","year":"2020","unstructured":"Searle, B. C. et al. Generating high quality libraries for DIA MS with empirically corrected peptide predictions. Nat. Commun. 11, 1548 (2020).","journal-title":"Nat. Commun."},{"key":"1799_CR84","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/nbt.2377","volume":"30","author":"MC Chambers","year":"2012","unstructured":"Chambers, M. C. et al. A cross-platform toolkit for mass spectrometry and proteomics. Nat. Biotechnol. 30, 918\u2013920 (2012).","journal-title":"Nat. Biotechnol."},{"key":"1799_CR85","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","volume":"17","author":"V Demichev","year":"2020","unstructured":"Demichev, V., Messner, C. B., Vernardis, S. I., Lilley, K. S. & Ralser, M. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat. Methods 17, 41\u201344 (2020).","journal-title":"Nat. Methods"},{"key":"1799_CR86","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nmeth.3901","volume":"13","author":"S Tyanova","year":"2016","unstructured":"Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731\u2013740 (2016).","journal-title":"Nat. Methods"},{"key":"1799_CR87","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1471-2105-10-48","volume":"10","author":"E Eden","year":"2009","unstructured":"Eden, E., Navon, R., Steinfeld, I., Lipson, D. & Yakhini, Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinform. 10, 48 (2009).","journal-title":"BMC Bioinform."},{"key":"1799_CR88","doi-asserted-by":"crossref","first-page":"D543","DOI":"10.1093\/nar\/gkab1038","volume":"50","author":"Y Perez-Riverol","year":"2021","unstructured":"Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543\u2013D552 (2021).","journal-title":"Nucleic Acids Res."},{"key":"1799_CR89","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1038\/nprot.2016.106","volume":"11","author":"M Koopman","year":"2016","unstructured":"Koopman, M. et al. A screening-based platform for the assessment of cellular respiration in Caenorhabditis elegans. Nat. Protoc. 11, 1798\u20131816 (2016).","journal-title":"Nat. Protoc."},{"key":"1799_CR90","doi-asserted-by":"crossref","first-page":"100245","DOI":"10.1016\/j.xpro.2020.100245","volume":"2","author":"X Gu","year":"2021","unstructured":"Gu, X., Ma, Y., Liu, Y. & Wan, Q. Measurement of mitochondrial respiration in adherent cells by Seahorse XF96 cell mito stress test. STAR Protoc. 2, 100245 (2021).","journal-title":"STAR Protoc."},{"key":"1799_CR91","doi-asserted-by":"publisher","unstructured":"Kwah, J. K. & Jaramillo-Lambert, A. Measuring embryonic viability and brood size in Caenorhabditis elegans. J. Vis. Exp. https:\/\/doi.org\/10.3791\/65064 (2023).","DOI":"10.3791\/65064"},{"key":"1799_CR92","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.cell.2015.07.016","volume":"162","author":"K Birsoy","year":"2015","unstructured":"Birsoy, K. et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540\u2013551 (2015).","journal-title":"Cell"}],"container-title":["Nature Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41556-025-01799-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41556-025-01799-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41556-025-01799-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T12:03:34Z","timestamp":1762949014000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41556-025-01799-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":92,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["1799"],"URL":"https:\/\/doi.org\/10.1038\/s41556-025-01799-3","relation":{},"ISSN":["1465-7392","1476-4679"],"issn-type":[{"value":"1465-7392","type":"print"},{"value":"1476-4679","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,31]]},"assertion":[{"value":"17 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}