{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T01:29:19Z","timestamp":1794274159178,"version":"4.9.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70<jats:sup>Ser91<\/jats:sup> by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70<jats:sup>Ser91<\/jats:sup> phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional <jats:italic>DYRK1A<\/jats:italic>, including autism spectrum disorder, microcephaly and Down syndrome.<\/jats:p>","DOI":"10.1038\/s41467-021-24426-9","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T10:24:02Z","timestamp":1626171842000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery"],"prefix":"10.1038","volume":"12","author":[{"given":"Corvin","family":"Walter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adinarayana","family":"Marada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Suhm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Ernsberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Muders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cansu","family":"K\u00fcc\u00fckk\u00f6se","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"S\u00e1nchez-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-4781","authenticated-orcid":false,"given":"Zehan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8331-9874","authenticated-orcid":false,"given":"Abhishek","family":"Aich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Loroch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorella Andrea","family":"Solari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4747-9237","authenticated-orcid":false,"given":"Daniel","family":"Poveda-Huertes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Schwierzok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrike","family":"Pommerening","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanka","family":"Matic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Brix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2388-5265","authenticated-orcid":false,"given":"Albert","family":"Sickmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3324-4701","authenticated-orcid":false,"given":"Claudine","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9453-4614","authenticated-orcid":false,"given":"J\u00f6rn","family":"Dengjel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Dennerlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-7905","authenticated-orcid":false,"given":"Tilman","family":"Brummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.-Nora","family":"V\u00f6gtle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8326-3548","authenticated-orcid":false,"given":"Chris","family":"Meisinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"24426_CR1","doi-asserted-by":"publisher","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":"24426_CR2","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.cell.2008.06.016","volume":"134","author":"DJ Pagliarini","year":"2008","unstructured":"Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112\u2013123 (2008).","journal-title":"Cell"},{"key":"24426_CR3","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/j.cell.2009.08.005","volume":"138","author":"A Chacinska","year":"2009","unstructured":"Chacinska, A., Koehler, C. M., Milenkovic, D., Lithgow, T. & Pfanner, N. Importing mitochondrial proteins: machineries and mechanisms. Cell 138, 628\u2013644 (2009).","journal-title":"Cell"},{"key":"24426_CR4","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.cell.2008.06.043","volume":"134","author":"C Meisinger","year":"2008","unstructured":"Meisinger, C., Sickmann, A. & Pfanner, N. The mitochondrial proteome: from inventory to function. Cell 134, 22\u201324 (2008).","journal-title":"Cell"},{"key":"24426_CR5","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1146\/annurev-genom-082509-141720","volume":"11","author":"SE Calvo","year":"2010","unstructured":"Calvo, S. E. & Mootha, V. K. The mitochondrial proteome and human disease. Annu. Rev. Genomics Hum. Genet. 11, 25\u201344 (2010).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"24426_CR6","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.cmet.2014.01.010","volume":"19","author":"AB Harbauer","year":"2014","unstructured":"Harbauer, A. B., Zahedi, R. P., Sickmann, A., Pfanner, N. & Meisinger, C. The protein import machinery of mitochondria - a regulatory hub in metabolism, stress, and disease. Cell Metab. 19, 357\u2013372 (2014).","journal-title":"Cell Metab."},{"key":"24426_CR7","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1515\/BC.2009.087","volume":"390","author":"T Endo","year":"2009","unstructured":"Endo, T. & Yamano, K. Multiple pathways for mitochondrial protein traffic. Biol. Chem. 390, 723\u2013730 (2009).","journal-title":"Biol. Chem."},{"key":"24426_CR8","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/j.cell.2009.07.045","volume":"139","author":"FN V\u00f6gtle","year":"2009","unstructured":"V\u00f6gtle, F. N. et al. Global analysis of the mitochondrial N-Proteome identifies a processing peptidase critical for protein stability. Cell 139, 428\u2013439 (2009).","journal-title":"Cell"},{"key":"24426_CR9","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/s41586-019-1680-7","volume":"575","author":"Y Araiso","year":"2019","unstructured":"Araiso, Y. et al. Structure of the mitochondrial import gate reveals distinct preprotein paths. Nature 575, 395\u2013401 (2019).","journal-title":"Nature"},{"key":"24426_CR10","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1111\/bph.14480","volume":"176","author":"M Habich","year":"2019","unstructured":"Habich, M., Salscheider, S. L. & Riemer, J. Cysteine residues in mitochondrial intermembrane space proteins: more than just import. Br. J. Pharmacol. 176, 514\u2013531 (2019).","journal-title":"Br. J. Pharmacol."},{"key":"24426_CR11","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1038\/s41594-019-0339-2","volume":"26","author":"K Tucker","year":"2019","unstructured":"Tucker, K. & Park, E. Cryo-EM structure of the mitochondrial protein-import channel TOM complex at near-atomic resolution. Nat. Struct. Mol. Biol. 26, 1158\u20131166 (2019).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"24426_CR12","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1515\/hsz-2019-0440","volume":"401","author":"L Drwesh","year":"2020","unstructured":"Drwesh, L. & Rapaport, D. Biogenesis pathways of \u03b1-helical mitochondrial outer membrane proteins. Biol. Chem. 401, 677\u2013686 (2020).","journal-title":"Biol. Chem."},{"key":"24426_CR13","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1515\/hsz-2019-0444","volume":"401","author":"A Schneider","year":"2020","unstructured":"Schneider, A. Evolution of mitochondrial protein import \u2013 lessons from trypanosomes. Biol. Chem. 401, 663\u2013676 (2020).","journal-title":"Biol. Chem."},{"key":"24426_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00359-0","volume":"8","author":"FN V\u00f6gtle","year":"2017","unstructured":"V\u00f6gtle, F. N. et al. Landscape of submitochondrial protein distribution. Nat. Commun. 8, 290 (2017).","journal-title":"Nat. Commun."},{"key":"24426_CR15","doi-asserted-by":"publisher","first-page":"20730","DOI":"10.1074\/jbc.272.33.20730","volume":"272","author":"J Brix","year":"1997","unstructured":"Brix, J., Dietmeier, K. & Pfanner, N. Differential recognition of preproteins by the purified cytosolic domains of the mitochondrial import receptors Tom20, Tom22, and Tom70. J. Biol. Chem. 272, 20730\u201320735 (1997).","journal-title":"J. Biol. Chem."},{"key":"24426_CR16","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1093\/emboj\/20.5.951","volume":"20","author":"N Wiedemann","year":"2001","unstructured":"Wiedemann, N., Pfanner, N. & Ryan, M. T. The three modules of ADP\/ATP carrier cooperate in receptor recruitment and translocation into mitochondria. EMBO J. 20, 951\u2013960 (2001).","journal-title":"EMBO J."},{"key":"24426_CR17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0092-8674(02)01250-3","volume":"112","author":"JC Young","year":"2003","unstructured":"Young, J. C., Hoogenraad, N. J. & Hartl, F. U. Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112, 41\u201350 (2003).","journal-title":"Cell"},{"key":"24426_CR18","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.bbabio.2008.03.008","volume":"1777","author":"F Palmieri","year":"2008","unstructured":"Palmieri, F. Diseases caused by defects of mitochondrial carriers: A review. Biochim. Biophys. Acta 1777, 564\u2013578 (2008).","journal-title":"Biochim. Biophys. Acta"},{"key":"24426_CR19","doi-asserted-by":"publisher","first-page":"31635","DOI":"10.1074\/jbc.M109.041756","volume":"284","author":"H Yamamoto","year":"2009","unstructured":"Yamamoto, H. et al. Roles of Tom70 in import of presequence-containing mitochondrial proteins. J. Biol. Chem. 284, 31635\u201331646 (2009).","journal-title":"J. Biol. Chem."},{"key":"24426_CR20","doi-asserted-by":"publisher","first-page":"2533","DOI":"10.1042\/BCJ20160627","volume":"474","author":"L MacPherson","year":"2018","unstructured":"MacPherson, L. & Tokatlidis, K. Protein trafficking in the mitochondrial intermembrane space: mechanisms and links to human disease. Biochem. J. 474, 2533\u20132545 (2018).","journal-title":"Biochem. J."},{"key":"24426_CR21","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1083\/jcb.201708044","volume":"217","author":"S Backes","year":"2018","unstructured":"Backes, S. et al. Tom70 enhances mitochondrial preprotein import efficiency by binding to internal targeting sequences. J. Cell Biol. 217, 1369\u20131382 (2018).","journal-title":"J. Cell Biol."},{"key":"24426_CR22","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1038\/384582a0","volume":"384","author":"C Sirrenberg","year":"1996","unstructured":"Sirrenberg, C., Bauer, M. F., Guiard, B., Neupert, W. & Brunner, M. Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22. Nature 384, 582\u2013585 (1996).","journal-title":"Nature"},{"key":"24426_CR23","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1126\/science.1080945","volume":"299","author":"P Rehling","year":"2006","unstructured":"Rehling, P. et al. Protein insertion into the mitochondrial inner membrane by a twin-pore translocase. Science 299, 1747\u20131751 (2006).","journal-title":"Science"},{"key":"24426_CR24","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.molcel.2017.06.014","volume":"67","author":"Y Kang","year":"2017","unstructured":"Kang, Y. et al. Sengers Syndrome-associated mitochondrial acylglycerol kinase is a subunit of the human TIM22 protein import complex. Mol. Cell 67, 457\u2013470 (2017).","journal-title":"Mol. Cell"},{"key":"24426_CR25","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.molcel.2017.06.013","volume":"67","author":"M Vukotic","year":"2017","unstructured":"Vukotic, M. et al. Acylglycerol kinase mutated in Sengers Syndrome is a subunit of the TIM22 protein translocase in mitochondria. Mol. Cell 67, 471\u2013483 (2017).","journal-title":"Mol. Cell"},{"key":"24426_CR26","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.tcb.2014.12.001","volume":"25","author":"C Schulz","year":"2015","unstructured":"Schulz, C., Schendzielorz, A. & Rehling, P. Unlocking the presequence import pathway. Trends Cell Biol. 25, 265\u2013175 (2015).","journal-title":"Trends Cell Biol."},{"key":"24426_CR27","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1007\/s10930-019-09819-6","volume":"38","author":"KG Hansen","year":"2019","unstructured":"Hansen, K. G. & Herrmann, J. M. Transport of proteins into mitochondria. Protein J. 38, 330\u2013342 (2019).","journal-title":"Protein J."},{"key":"24426_CR28","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1515\/hsz-2020-0101","volume":"401","author":"S Callegari","year":"2020","unstructured":"Callegari, S., Cruz-Zaragoza, L. D. & Rehling, P. From TOM to the TIM23 complex \u2013 handing over a precursor. Biol. Chem. 401, 709\u2013721 (2020).","journal-title":"Biol. Chem."},{"key":"24426_CR29","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1128\/MCB.21.7.2337-2348.2001","volume":"21","author":"C Meisinger","year":"2001","unstructured":"Meisinger, C. et al. Protein import channel of the outer mitochondrial membrane: a highly stable Tom40-Tom22 core structure differentially interacts with preproteins, small Tom proteins, and import receptors. Mol. Cell. Biol. 21, 2337\u20132348 (2001).","journal-title":"Mol. Cell. Biol."},{"key":"24426_CR30","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1016\/j.jmb.2006.02.062","volume":"358","author":"NC Chan","year":"2006","unstructured":"Chan, N. C., Likic, V. A., Waller, R. F., Mulhern, T. D. & Lithgow, T. The C-terminal TPR domain of Tom70 defines a family of mitochondrial protein import receptors found only in animals and fungi. J. Mol. Biol. 358, 1010\u20131022 (2006).","journal-title":"J. Mol. Biol."},{"key":"24426_CR31","doi-asserted-by":"publisher","first-page":"32208","DOI":"10.1074\/jbc.M111.280446","volume":"286","author":"ACY Fan","year":"2011","unstructured":"Fan, A. C. Y. et al. Interaction between the human mitochondrial import receptors Tom20 and Tom70 in vitro suggests a chaperone displacement mechanism. J. Biol. Chem. 286, 32208\u201332219 (2011).","journal-title":"J. Biol. Chem."},{"key":"24426_CR32","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1016\/j.bbamcr.2015.04.021","volume":"1853","author":"J Melin","year":"2015","unstructured":"Melin, J. et al. A presequence-binding groove in Tom70 supports import of Mdl1 into mitochondria. Biochim. Biophys. Acta 1853, 1850\u20131859 (2015).","journal-title":"Biochim. Biophys. Acta"},{"key":"24426_CR33","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.cell.2010.12.015","volume":"144","author":"O Schmidt","year":"2011","unstructured":"Schmidt, O. et al. Regulation of mitochondrial protein import by cytosolic kinases. Cell 144, 227\u2013239 (2011).","journal-title":"Cell"},{"key":"24426_CR34","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.cmet.2013.09.006","volume":"18","author":"C Gerbeth","year":"2013","unstructured":"Gerbeth, C. et al. Glucose-induced regulation of protein import receptor Tom22 by cytosolic and mitochondria-bound kinases. Cell Metab. 18, 578\u2013587 (2013).","journal-title":"Cell Metab."},{"key":"24426_CR35","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1126\/science.1261253","volume":"346","author":"AB Harbauer","year":"2014","unstructured":"Harbauer, A. B. et al. Mitochondria. Cell cycle-dependent regulation of mitochondrial preprotein translocase. Science 346, 1109\u20131113 (2014).","journal-title":"Science"},{"key":"24426_CR36","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/470163a","volume":"470","author":"AM Edwards","year":"2011","unstructured":"Edwards, A. M. et al. Too many roads not taken. Nature 470, 163\u2013165 (2011).","journal-title":"Nature"},{"key":"24426_CR37","doi-asserted-by":"publisher","first-page":"3235","DOI":"10.1007\/s00018-009-0123-2","volume":"66","author":"J Park","year":"2009","unstructured":"Park, J., Song, W. J. & Chung, K. C. Function and regulation of Dyrk1A: towards understanding Down syndrome. Cell. Mol. Life Sci. 66, 3235\u20133240 (2009).","journal-title":"Cell. Mol. Life Sci."},{"key":"24426_CR38","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1002\/ajmg.a.33735","volume":"155A","author":"T Yamamoto","year":"2011","unstructured":"Yamamoto, T. et al. Clinical manifestations of the deletion of Down syndrome critical region including DYRK1A and KCNJ6. Am. J. Med. Genet. A 155A, 113\u2013119 (2011).","journal-title":"Am. J. Med. Genet. A"},{"key":"24426_CR39","doi-asserted-by":"publisher","first-page":"236245","DOI":"10.1111\/j.1742-4658.2010.07955.x","volume":"278","author":"J Wegiel","year":"2011","unstructured":"Wegiel, J., Gong, C. X. & Hwang, Y. W. The role of DYRK1A in neurodegenerative diseases. FEBS J. 278, 236245 (2011).","journal-title":"FEBS J."},{"key":"24426_CR40","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1111\/j.1399-0004.2010.01544.x","volume":"79","author":"BW van Bon","year":"2011","unstructured":"van Bon, B. W. et al. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin. Genet. 79, 296\u2013299 (2011).","journal-title":"Clin. Genet."},{"key":"24426_CR41","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1136\/jmedgenet-2012-101251","volume":"49","author":"JB Courcet","year":"2012","unstructured":"Courcet, J. B. et al. The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. J. Med. Genet. 49, 731\u2013736 (2012).","journal-title":"J. Med. Genet."},{"key":"24426_CR42","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1038\/ejhg.2015.71","volume":"23","author":"J Ji","year":"2015","unstructured":"Ji, J. et al. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur. J. Hum. Genet. 23, 1473\u20131481 (2015).","journal-title":"Eur. J. Hum. Genet."},{"key":"24426_CR43","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1006\/scdb.2001.0278","volume":"12","author":"M Zeviani","year":"2001","unstructured":"Zeviani, M. The expanding spectrum of nuclear gene mutations in mitochondrial disorders. Semin. Cell Dev. Biol. 12, 407\u2013416 (2001).","journal-title":"Semin. Cell Dev. Biol."},{"key":"24426_CR44","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1016\/j.cell.2012.02.035","volume":"148","author":"J Nunnari","year":"2012","unstructured":"Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145\u20131159 (2012).","journal-title":"Cell"},{"key":"24426_CR45","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.1101\/gad.229724.113","volume":"27","author":"DJ Pagliarini","year":"2013","unstructured":"Pagliarini, D. J. & Rutter, J. Hallmarks of a new era in mitochondrial biochemistry. Genes Dev. 27, 2615\u20132627 (2013).","journal-title":"Genes Dev."},{"key":"24426_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/srep26965","volume":"6","author":"E Butkevich","year":"2016","unstructured":"Butkevich, E. et al. Phosphorylation of FEZ1 by microtubule affinity regulating kinases regulates its function in presynaptic protein trafficking. Sci. Rep. 6, 26965 (2016).","journal-title":"Sci. Rep."},{"key":"24426_CR47","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1074\/mcp.T500024-MCP200","volume":"5","author":"E Kinoshita","year":"2006","unstructured":"Kinoshita, E., Kinoshita-Kikuta, E., Takiyama, K. & Koike, T. Phosphate-binding tag, a new tool to visualize phosphorylated proteins. Mol. Cell Proteom. 5, 749\u2013757 (2006).","journal-title":"Mol. Cell Proteom."},{"key":"24426_CR48","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ab.2018.05.022","volume":"554","author":"C Walter","year":"2018","unstructured":"Walter, C. et al. Advanced tools for the analysis of protein phosphorylation in yeast mitochondria. Anal. Biochem. 554, 23\u201327 (2018).","journal-title":"Anal. Biochem."},{"key":"24426_CR49","doi-asserted-by":"publisher","first-page":"R483","DOI":"10.1016\/j.cub.2015.02.067","volume":"25","author":"U Soppa","year":"2015","unstructured":"Soppa, U. & Becker, W. DYRK protein kinases. Curr. Biol. 25, R483\u2013R489 (2015).","journal-title":"Curr. Biol."},{"key":"24426_CR50","doi-asserted-by":"publisher","first-page":"e970048","DOI":"10.4161\/23723548.2014.970048","volume":"2","author":"P Fern\u00e1ndez-Martinez","year":"2015","unstructured":"Fern\u00e1ndez-Martinez, P., Zahonero, C. & S\u00e1nchez-G\u00f3mez, P. DYRK1A: the doubleedged kinase as a protagonist in cell growth and tumorigenesis. Mol. Cell. Oncol. 2, e970048 (2015).","journal-title":"Mol. Cell. Oncol."},{"key":"24426_CR51","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1515\/hsz-2013-0264","volume":"295","author":"ML Schmitz","year":"2014","unstructured":"Schmitz, M. L., Rodriguez-Gil, A. & Hornung, J. Integration of stress signals by homeodomain interacting protein kinases. Biol. Chem. 295, 375\u2013386 (2014).","journal-title":"Biol. Chem."},{"key":"24426_CR52","doi-asserted-by":"publisher","DOI":"10.1242\/dev.189290","author":"HR Willsey","year":"2020","unstructured":"Willsey, H. R. et al. Neurodevelopmental disorder risk gene DYRK1A is required for ciliogenesis and brain size in Xenopus embryos. Development https:\/\/doi.org\/10.1242\/dev.189290 (2020).","journal-title":"Development"},{"key":"24426_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1090","volume":"1","author":"Y Ogawa","year":"2010","unstructured":"Ogawa, Y. et al. Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nat. Commun. 1, 86 (2010).","journal-title":"Nat. Commun."},{"key":"24426_CR54","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1016\/j.cub.2020.01.024","volume":"30","author":"R Gomkale","year":"2020","unstructured":"Gomkale, R. et al. Defining the substrate spectrum of the TIM22 complex identifies pyruvate carrier subunits as unconventional cargos. Curr. Biol. 30, 1119\u20131127 (2020).","journal-title":"Curr. Biol."},{"key":"24426_CR55","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1016\/j.cmet.2014.07.024","volume":"20","author":"D Mossmann","year":"2014","unstructured":"Mossmann, D. et al. Amyloid-\u03b2 peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab. 20, 662\u2013669 (2014).","journal-title":"Cell Metab."},{"key":"24426_CR56","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15358","author":"C K\u00fcc\u00fckk\u00f6se","year":"2020","unstructured":"K\u00fcc\u00fckk\u00f6se, C. et al. Functional coupling of presequence processing and degradation in human mitochondria. FEBS J. https:\/\/doi.org\/10.1111\/febs.15358 (2020).","journal-title":"FEBS J."},{"key":"24426_CR57","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/376705a0","volume":"376","author":"N Hachiya","year":"1995","unstructured":"Hachiya, N. et al. Reconstitution of the initial steps of mitochondrial protein import. Nature 376, 705\u2013709 (1995).","journal-title":"Nature"},{"key":"24426_CR58","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1038\/421801a","volume":"421","author":"RJ Ellis","year":"2003","unstructured":"Ellis, R. J. Plugging the transport gap. Nature 421, 801\u2013802 (2003).","journal-title":"Nature"},{"key":"24426_CR59","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1038\/nprot.2013.143","volume":"8","author":"FA Ran","year":"2013","unstructured":"Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281\u20132308 (2013).","journal-title":"Nat. Protoc."},{"key":"24426_CR60","doi-asserted-by":"publisher","first-page":"42197","DOI":"10.1074\/jbc.M205613200","volume":"277","author":"AJ Johnston","year":"2002","unstructured":"Johnston, A. J. et al. Insertion and assembly of human tom7 into the preprotein translocase complex of the outer mitochondrial membrane. J. Biol. Chem. 277, 42197\u201342204 (2002).","journal-title":"J. Biol. Chem."},{"key":"24426_CR61","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1038\/nsb726","volume":"8","author":"KN Truscott","year":"2001","unstructured":"Truscott, K. N. et al. A presequence- and voltage-sensitive channel of the mitochondrial preprotein translocase formed by Tim23. Nat. Struct. Biol. 8, 1074\u20131082 (2001).","journal-title":"Nat. Struct. Biol."},{"key":"24426_CR62","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/S0091-679X(06)80036-1","volume":"80","author":"D Stojanovski","year":"2007","unstructured":"Stojanovski, D., Pfanner, N. & Wiedemann, N. Import of proteins into mitochondria. Methods Cell Biol. 80, 783\u2013806 (2007).","journal-title":"Methods Cell Biol."},{"key":"24426_CR63","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jneumeth.2016.01.008","volume":"262","author":"L Wiemerslage","year":"2016","unstructured":"Wiemerslage, L. & Lee, D. Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters. J. Neurosci. Methods 262, 56\u201365 (2016).","journal-title":"J. Neurosci. Methods"},{"key":"24426_CR64","doi-asserted-by":"publisher","first-page":"3486","DOI":"10.1016\/j.celrep.2019.08.069","volume":"28","author":"Z Hu","year":"2019","unstructured":"Hu, Z. et al. Multilayered control of protein turnover by TORC1 and Atg1. Cell Rep. 28, 3486\u20133496 (2019).","journal-title":"Cell Rep."},{"key":"24426_CR65","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nprot.2015.134","volume":"11","author":"M Zarei","year":"2016","unstructured":"Zarei, M., Sprenger, A., Rackiewicz, M. & Dengjel, J. Fast and easy phosphopeptide fractionation by combinatorial ERLIC-SCX solid-phase extraction for in-depth phosphoproteome analysis. Nat. Protoc. 11, 37\u201345 (2016).","journal-title":"Nat. Protoc."},{"key":"24426_CR66","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1038\/nbt.1511","volume":"26","author":"J Cox","year":"2008","unstructured":"Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367\u20131372 (2008).","journal-title":"Nat. Biotechnol."},{"key":"24426_CR67","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1016\/j.jprot.2011.11.016","volume":"75","author":"JM Burkhart","year":"2012","unstructured":"Burkhart, J. M., Schumbrutzki, C., Wortelkamp, S., Sickmann, A. & Zahedi, R. P. Systematic and quantitative comparison of digest efficiency and specificity reveals the impact of trypsin quality on MS-based proteomics. J. Proteom. 75, 1454\u20131462 (2012).","journal-title":"J. Proteom."},{"key":"24426_CR68","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.bbapap.2015.01.006","volume":"1854","author":"S Loroch","year":"2015","unstructured":"Loroch, S., Schommartz, T., Brune, W., Zahedi, R. P. & Sickmann, A. Multidimensional electrostatic repulsion-hydrophilic interaction chromatography (ERLIC) for quantitative analysis of the proteome and phosphoproteome in clinical and biomedical research. Biochim. Biophys. Acta 1854, 460\u2013468 (2015).","journal-title":"Biochim. Biophys. Acta"},{"key":"24426_CR69","doi-asserted-by":"publisher","first-page":"5354","DOI":"10.1021\/pr200611n","volume":"10","author":"T Taus","year":"2011","unstructured":"Taus, T. et al. Universal and confident phosphorylation site localization using phosphoRS. J. Proteome Res. 10, 5354\u20135362 (2011).","journal-title":"J. Proteome Res."},{"key":"24426_CR70","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1038\/nmeth1113","volume":"4","author":"L Kall","year":"2007","unstructured":"Kall, L., Canterbury, J. D., Weston, J., Noble, W. S. & MacCoss, M. J. Semi-supervised learning for peptide identification from shotgun proteomics datasets. Nat. Methods 4, 923\u2013925 (2007).","journal-title":"Nat. Methods"},{"key":"24426_CR71","doi-asserted-by":"publisher","first-page":"D442","DOI":"10.1093\/nar\/gky1106","volume":"47","author":"Y Perez-Riverol","year":"2019","unstructured":"Perez-Riverol, Y. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res 47, D442\u2013D450 (2019).","journal-title":"Nucleic Acids Res"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-24426-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-24426-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-24426-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T13:24:38Z","timestamp":1669987478000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-24426-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,13]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["24426"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-24426-9","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,13]]},"assertion":[{"value":"7 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2021","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"}}],"article-number":"4284"}}