{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:11:02Z","timestamp":1793315462933,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T00:00:00Z","timestamp":1573084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Baron Munchausen Program of the Department of Medical Chemistry, Molecular Biology and Pathobiochemistry of Semmelweis University","award":["Department of Medical Chemistry, Molecular Biology and Pathobiochemistry of Semmelweis University"],"award-info":[{"award-number":["Department of Medical Chemistry, Molecular Biology and Pathobiochemistry of Semmelweis University"]}]},{"name":"New National Excellence Program of the Ministry of Human Capacities, by the National Research, Development and Innovation Office","award":["\u00daNKP-18-3-I-SE-19"],"award-info":[{"award-number":["\u00daNKP-18-3-I-SE-19"]}]},{"name":"EFOP-3.6.3-VEKOP","award":["EFOP-3.6.3-VEKOP-16-2017-00009"],"award-info":[{"award-number":["EFOP-3.6.3-VEKOP-16-2017-00009"]}]},{"name":"Semmelweis University, Budapest","award":["STIA_18_KF"],"award-info":[{"award-number":["STIA_18_KF"]}]},{"DOI":"10.13039\/501100003825","name":"Hungarian Academy of Sciences","doi-asserted-by":"publisher","award":["MedInProt"],"award-info":[{"award-number":["MedInProt"]}],"id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cellular homeostasis is controlled by an evolutionary conserved cellular digestive process called autophagy. This mechanism is tightly regulated by the two sensor elements called mTORC1 and AMPK. mTORC1 is one of the master regulators of proteostasis, while AMPK maintains cellular energy homeostasis. AMPK is able to promote autophagy by phosphorylating ULK1, the key inducer of autophagosome formation, while mTORC1 downregulates the self-eating process via ULK1 under nutrient rich conditions. We claim that the feedback loops of the AMPK\u2013mTORC1\u2013ULK1 regulatory triangle guarantee the appropriate response mechanism when nutrient and\/or energy supply changes. In our opinion, there is an essential double negative feedback loop between mTORC1 and AMPK. Namely, not only does AMPK downregulate mTORC1, but mTORC1 also inhibits AMPK and this inhibition is required to keep AMPK inactive at physiological conditions. The aim of the present study was to explore the dynamical characteristic of AMPK regulation upon various cellular stress events. We approached our scientific analysis from a systems biology perspective by incorporating both theoretical and molecular biological techniques. In this study, we confirmed that AMPK is essential to promote autophagy, but is not sufficient to maintain it. AMPK activation is followed by ULK1 induction, where protein has a key role in keeping autophagy active. ULK1-controlled autophagy is always preceded by AMPK activation. With both ULK1 depletion and mTORC1 hyper-activation (i.e., TSC1\/2 downregulation), we demonstrate that a double negative feedback loop between AMPK and mTORC1 is crucial for the proper dynamic features of the control network. Our computer simulations have further proved the dynamical characteristic of AMPK\u2013mTORC1\u2013ULK1 controlled cellular nutrient sensing.<\/jats:p>","DOI":"10.3390\/ijms20225543","type":"journal-article","created":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T06:52:36Z","timestamp":1573109556000},"page":"5543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress"],"prefix":"10.3390","volume":"20","author":[{"given":"Marianna","family":"Holczer","sequence":"first","affiliation":[{"name":"Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bence","family":"Hajd\u00fa","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-4007","authenticated-orcid":false,"given":"Tam\u00e1s","family":"L\u0151rincz","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Szarka","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"B\u00e1nhegyi","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1085 Budapest, Hungary"},{"name":"Pathobiochemistry Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsolya","family":"Kapuy","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrm2239","article-title":"Self-eating and self-killing: Crosstalk between autophagy and apoptosis","volume":"8","author":"Maiuri","year":"2007","journal-title":"Nat. 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