{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:09:54Z","timestamp":1791086994470,"version":"4.1.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J. Math. Biol."],"published-print":{"date-parts":[[2026,9]]},"DOI":"10.1007\/s00285-026-02441-y","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T15:52:35Z","timestamp":1786031555000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["When reoxygenation fails: a dynamical model of HIF-1$$\\alpha $$-mediated metabolic breakdown under hypoxia and SARS-CoV-2 infection"],"prefix":"10.1007","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6958-0854","authenticated-orcid":false,"given":"Alexander","family":"Ryvkin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1104-4338","authenticated-orcid":false,"given":"Yuri","family":"Kogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"issue":"1","key":"2441_CR1","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1080\/22221751.2020.1799723","volume":"9","author":"S Appelberg","year":"2020","unstructured":"Appelberg S, Gupta S, Svensson Akusj\u00e4rvi S, Ambikan AT, Mikaeloff F, Saccon E, Vegvari A, Benfeitas R, Sperk M, St\u00e5hlberg M et al (2020) Dysregulation in Akt\/mTOR\/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg Microbes Infect 9(1):1748\u20131760. https:\/\/doi.org\/10.1080\/22221751.2020.1799723","journal-title":"Emerg Microbes Infect"},{"issue":"6","key":"2441_CR2","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1083\/jcb.200609074","volume":"177","author":"EL Bell","year":"2007","unstructured":"Bell EL, Klimova TA, Eisenbart J, Moraes CT, Murphy MP, Budinger GRS, Chandel NS (2007) The $$\\text{ q}_o$$ site of the mitochondrial complex iii is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 177(6):1029\u20131036. https:\/\/doi.org\/10.1083\/jcb.200609074","journal-title":"J Cell Biol"},{"issue":"33","key":"2441_CR3","doi-asserted-by":"publisher","first-page":"25130","DOI":"10.1074\/jbc.M001914200","volume":"275","author":"NS Chandel","year":"2000","unstructured":"Chandel NS, Maltepe E, Goldwasser E, Mathieu J, Simon MC, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex iii stabilize hypoxia-inducible factor-1$$\\alpha $$ during hypoxia: a mechanism of $$\\text{ o}_2$$ sensing. J Biol Chem 275(33):25130\u201325138. https:\/\/doi.org\/10.1074\/jbc.M001914200","journal-title":"J Biol Chem"},{"issue":"3","key":"2441_CR4","doi-asserted-by":"publisher","first-page":"2606","DOI":"10.3390\/ijms24032606","volume":"24","author":"C Chelakkot","year":"2023","unstructured":"Chelakkot C, Ghim J, Ryu SH (2023) Modulating glycolysis to improve cancer therapy. Int J Mol Sci 24(3):2606. https:\/\/doi.org\/10.3390\/ijms24032606","journal-title":"Int J Mol Sci"},{"issue":"15","key":"2441_CR5","doi-asserted-by":"publisher","first-page":"24840","DOI":"10.18632\/oncotarget.15266","volume":"8","author":"X Cui","year":"2017","unstructured":"Cui X, Han Z, Li F, Li Y, Yang X, Liu C, Liu Z, Wang D (2017) Hif1\/2$$\\alpha $$ mediates hypoxia-induced LDHA expression in human pancreatic cancer cells. Oncotarget 8(15):24840\u201324852. https:\/\/doi.org\/10.18632\/oncotarget.15266","journal-title":"Oncotarget"},{"issue":"10","key":"2441_CR6","doi-asserted-by":"publisher","first-page":"46571","DOI":"10.1371\/journal.pone.0046571","volume":"7","author":"CJ De Saedeleer","year":"2012","unstructured":"De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P (2012) Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS ONE 7(10):46571. https:\/\/doi.org\/10.1371\/journal.pone.0046571","journal-title":"PLoS ONE"},{"issue":"4","key":"2441_CR7","doi-asserted-by":"publisher","first-page":"70","DOI":"10.3390\/medsci11040070","volume":"11","author":"A Dushianthan","year":"2023","unstructured":"Dushianthan A, Bracegirdle L, Cusack R, Cumpstey AF, Postle AD, Grocott MPW (2023) Alveolar hyperoxia and exacerbation of lung injury in critically ill SARS-CoV-2 pneumonia. Med Sci 11(4):70. https:\/\/doi.org\/10.3390\/medsci11040070","journal-title":"Med Sci"},{"issue":"18","key":"2441_CR8","doi-asserted-by":"publisher","first-page":"9977","DOI":"10.3390\/ijms25189977","volume":"25","author":"W Eisenreich","year":"2024","unstructured":"Eisenreich W, Rudel T, Heesemann J (2024) Interactions of SARS-CoV-2 with human target cells-a metabolic view. Int J Mol Sci 25(18):9977. https:\/\/doi.org\/10.3390\/ijms25189977","journal-title":"Int J Mol Sci"},{"issue":"19","key":"2441_CR9","doi-asserted-by":"publisher","first-page":"2969","DOI":"10.3390\/cells11192969","volume":"11","author":"MI Faizan","year":"2022","unstructured":"Faizan MI, Chaudhuri R, Sagar S, Albogami S, Khurram M, Khan AA, Khan MA, Khan MF, Ansari SA, Siddiqui SS, Khurshid M (2022) NSP4 and ORF9b of SARS-CoV-2 induce pro-inflammatory mitochondrial DNA release in inner membrane-derived vesicles. Cells 11(19):2969. https:\/\/doi.org\/10.3390\/cells11192969","journal-title":"Cells"},{"issue":"1","key":"2441_CR10","doi-asserted-by":"publisher","first-page":"5208","DOI":"10.1038\/s41467-022-32871-3","volume":"13","author":"T Feng","year":"2022","unstructured":"Feng T, Zhao X, Gu P, Yang W, Wang C, Guo Q, Long Q, Liu Q, Cheng Y, Li J (2022) Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2. Nat Commun 13(1):5208. https:\/\/doi.org\/10.1038\/s41467-022-32871-3","journal-title":"Nat Commun"},{"key":"2441_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107170","volume":"204","author":"JW Guarnieri","year":"2024","unstructured":"Guarnieri JW, Dybas JM, Chung M, Kloc A, Rabinowitz JD, Schultz MB, Stanley SA (2024) SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19. Pharmacol Res 204:107170. https:\/\/doi.org\/10.1016\/j.phrs.2024.107170","journal-title":"Pharmacol Res"},{"key":"2441_CR12","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.899633","volume":"13","author":"Z Huang","year":"2022","unstructured":"Huang Z, Zhang J, Li Y (2022) 2-deoxy-d-glucose and its derivatives for the COVID-19 treatment: an update. Front Pharmacol 13:899633. https:\/\/doi.org\/10.3389\/fphar.2022.899633","journal-title":"Front Pharmacol"},{"issue":"1","key":"2441_CR13","doi-asserted-by":"publisher","first-page":"50","DOI":"10.3390\/biom13010050","volume":"13","author":"X Huang","year":"2022","unstructured":"Huang X, Zhao L, Peng R (2022) Hypoxia-inducible factor 1 and mitochondria: an intimate connection. Biomolecules 13(1):50. https:\/\/doi.org\/10.3390\/biom13010050","journal-title":"Biomolecules"},{"issue":"7","key":"2441_CR14","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1113\/EP089474","volume":"107","author":"UW Iepsen","year":"2022","unstructured":"Iepsen UW, Plovsing RR, Tjelle K, Foss NB, Meyhoff CS, Ryrs\u00f8 CK, Berg RMG, Secher NH (2022) The role of lactate in sepsis and COVID-19: perspective from contracting skeletal muscle metabolism. Exp Physiol 107(7):665\u2013673. https:\/\/doi.org\/10.1113\/EP089474","journal-title":"Exp Physiol"},{"issue":"11","key":"2441_CR15","doi-asserted-by":"publisher","first-page":"5703","DOI":"10.3390\/ijms22115703","volume":"22","author":"V Infantino","year":"2021","unstructured":"Infantino V, Dituri F, Convertini P, Todisco S, Maddalena F, Palmieri EM, Iacobazzi V (2021) Cancer cell metabolism in hypoxia: role of HIF-1 as key regulator and therapeutic target. Int J Mol Sci 22(11):5703. https:\/\/doi.org\/10.3390\/ijms22115703","journal-title":"Int J Mol Sci"},{"issue":"2","key":"2441_CR16","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1101\/gad.12.2.149","volume":"12","author":"NV Iyer","year":"1998","unstructured":"Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (1998) Cellular and developmental control of $$\\text{ O}_2$$ homeostasis by hypoxia-inducible factor 1$$\\alpha $$. Genes Dev 12(2):149\u2013162. https:\/\/doi.org\/10.1101\/gad.12.2.149","journal-title":"Genes Dev"},{"issue":"1","key":"2441_CR17","doi-asserted-by":"publisher","first-page":"558","DOI":"10.3390\/ijms24010558","volume":"24","author":"S Jana","year":"2023","unstructured":"Jana S, Kondakci E, Liu Y, Wang Y, Zhang Y, Lu S, Li X (2023) HIF-1$$\\alpha $$-dependent metabolic reprogramming, oxidative stress, and bioenergetic dysfunction in SARS-CoV-2-infected hamsters. Int J Mol Sci 24(1):558. https:\/\/doi.org\/10.3390\/ijms24010558","journal-title":"Int J Mol Sci"},{"issue":"9","key":"2441_CR18","doi-asserted-by":"publisher","first-page":"3909","DOI":"10.1073\/pnas.1816391116","volume":"116","author":"D Jia","year":"2019","unstructured":"Jia D, Lu M, Jung KH, Park JH, Yu L, Onuchic JN, Kaipparettu BA, Levine H (2019) Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways. Proc Natl Acad Sci 116(9):3909\u20133918. https:\/\/doi.org\/10.1073\/pnas.1816391116","journal-title":"Proc Natl Acad Sci"},{"issue":"3","key":"2441_CR19","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.cmet.2006.02.002","volume":"3","author":"JW Kim","year":"2006","unstructured":"Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177\u2013185. https:\/\/doi.org\/10.1016\/j.cmet.2006.02.002","journal-title":"Cell Metab"},{"issue":"1","key":"2441_CR20","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1007\/s40203-025-00336-2","volume":"13","author":"N Kumar","year":"2025","unstructured":"Kumar N, Singh A, Sharma P (2025) Molecular docking and pharmacological profiling of glycolytic inhibitors against SARS-CoV-2. In Silico Pharmacol 13(1):44. https:\/\/doi.org\/10.1007\/s40203-025-00336-2","journal-title":"In Silico Pharmacol"},{"key":"2441_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2025.112049","volume":"602","author":"K Larripa","year":"2025","unstructured":"Larripa K, R\u0103dulescu A (2025) A mathematical model of microglia glucose metabolism and Lactylation with positive feedback. J Theor Biol 602:112049. https:\/\/doi.org\/10.1016\/j.jtbi.2025.112049","journal-title":"J Theor Biol"},{"issue":"1","key":"2441_CR22","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/s41392-022-01151-3","volume":"7","author":"X Li","year":"2022","unstructured":"Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, Zou Y, Wang J-X, Wang Z, Yu T (2022) Lactate metabolism in human health and disease. Signal Transduct Target Ther 7(1):305. https:\/\/doi.org\/10.1038\/s41392-022-01151-3","journal-title":"Signal Transduct Target Ther"},{"issue":"7","key":"2441_CR23","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1038\/ncb1144","volume":"6","author":"K Mekhail","year":"2004","unstructured":"Mekhail K, Gunaratnam L, Bonicalzi M-E, Lee S (2004) HIF activation by pH-dependent nucleolar sequestration of VHL. Nat Cell Biol 6(7):642\u2013647. https:\/\/doi.org\/10.1038\/ncb1144","journal-title":"Nat Cell Biol"},{"issue":"4","key":"2441_CR24","doi-asserted-by":"publisher","first-page":"862","DOI":"10.3390\/cancers12040862","volume":"12","author":"NT Moldogazieva","year":"2020","unstructured":"Moldogazieva NT, Mokhosoev IM, Terentiev AA (2020) Metabolic heterogeneity of cancer cells: an interplay between HIF-1, GLUTs, and AMPK. Cancers 12(4):862. https:\/\/doi.org\/10.3390\/cancers12040862","journal-title":"Cancers"},{"issue":"3","key":"2441_CR25","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1002\/2211-5463.13765","volume":"14","author":"N Patil","year":"2024","unstructured":"Patil N, Mirveis Z, Byrne HJ (2024) Kinetic modelling of the cellular metabolic responses underpinning in vitro glycolysis assays. FEBS Open Bio 14(3):466\u2013486. https:\/\/doi.org\/10.1002\/2211-5463.13765","journal-title":"FEBS Open Bio"},{"issue":"5516","key":"2441_CR26","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1126\/science.1058079","volume":"292","author":"T Pfeiffer","year":"2001","unstructured":"Pfeiffer T, Schuster S, Bonhoeffer S (2001) Cooperation and competition in the evolution of ATP-producing pathways. Science 292(5516):504\u2013507. https:\/\/doi.org\/10.1126\/science.1058079","journal-title":"Science"},{"issue":"10","key":"2441_CR27","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1111\/j.1478-3231.2009.02109.x","volume":"29","author":"T Regueira","year":"2009","unstructured":"Regueira T, Lepper PM, Brandt S, Ochs M, Notz T, Kremer J-P, Nold MF (2009) HIF-1$$\\alpha $$ induction by TNF-$$\\alpha $$, but not by TLR agonists, modulates cellular respiration in cultured human hepatocytes. Liver Int 29(10):1582\u20131592. https:\/\/doi.org\/10.1111\/j.1478-3231.2009.02109.x","journal-title":"Liver Int"},{"key":"2441_CR28","doi-asserted-by":"publisher","first-page":"1406635","DOI":"10.3389\/fphys.2024.1406635","volume":"15","author":"M Rurek","year":"2024","unstructured":"Rurek M (2024) Mitochondria in COVID-19: from cellular and molecular perspective. Front Physiol 15:1406635. https:\/\/doi.org\/10.3389\/fphys.2024.1406635","journal-title":"Front Physiol"},{"key":"2441_CR29","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2021.685196","volume":"9","author":"AF Santos","year":"2021","unstructured":"Santos AF, P\u00f3voa P, Paiva JA, Moreira R (2021) Changes in glycolytic pathway in SARS-CoV-2 infection and their importance in understanding the severity of COVID-19. Front Chem 9:685196. https:\/\/doi.org\/10.3389\/fchem.2021.685196","journal-title":"Front Chem"},{"issue":"9","key":"2441_CR30","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1002\/iub.93","volume":"60","author":"GL Semenza","year":"2008","unstructured":"Semenza GL (2008) Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life 60(9):591\u2013597. https:\/\/doi.org\/10.1002\/iub.93","journal-title":"IUBMB Life"},{"issue":"12","key":"2441_CR31","doi-asserted-by":"publisher","first-page":"3930","DOI":"10.1172\/JCI36843","volume":"118","author":"P Sonveaux","year":"2008","unstructured":"Sonveaux P, V\u00e9gran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig 118(12):3930\u20133942. https:\/\/doi.org\/10.1172\/JCI36843","journal-title":"J Clin Investig"},{"issue":"7","key":"2441_CR32","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/s41556-018-0124-1","volume":"20","author":"JB Spinelli","year":"2018","unstructured":"Spinelli JB, Haigis MC (2018) The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol 20(7):745\u2013754. https:\/\/doi.org\/10.1038\/s41556-018-0124-1","journal-title":"Nat Cell Biol"},{"issue":"2","key":"2441_CR33","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1158\/0008-5472.CAN-11-2076","volume":"72","author":"X Tang","year":"2012","unstructured":"Tang X, Lucas JE, Chen JL-Y, LaMonte G, Wu J, Wang MC, Koumenis C, Chi J-T (2012) Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs. Can Res 72(2):491\u2013502. https:\/\/doi.org\/10.1158\/0008-5472.CAN-11-2076","journal-title":"Can Res"},{"issue":"5930","key":"2441_CR34","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1126\/science.1160809","volume":"324","author":"MG Vander Heiden","year":"2009","unstructured":"Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029\u20131033. https:\/\/doi.org\/10.1126\/science.1160809","journal-title":"Science"},{"issue":"3","key":"2441_CR35","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1152\/ajpcell.00485.2010","volume":"300","author":"WW Wheaton","year":"2011","unstructured":"Wheaton WW, Chandel NS (2011) Hypoxia. 2. hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol 300(3):385\u2013393. https:\/\/doi.org\/10.1152\/ajpcell.00485.2010","journal-title":"Am J Physiol Cell Physiol"},{"issue":"8","key":"2441_CR36","doi-asserted-by":"publisher","first-page":"202409103","DOI":"10.1083\/jcb.202409103","volume":"224","author":"B White","year":"2025","unstructured":"White B, Wang Z, Dean M, Michl J, Nieora N, Flannery S, Vendrell I, Fischer R, Hulikova A, Swietach P (2025) Acidosis attenuates the hypoxic stabilization of HIF-1$$\\alpha $$ by activating lysosomal degradation. J Cell Biol 224(8):202409103. https:\/\/doi.org\/10.1083\/jcb.202409103","journal-title":"J Cell Biol"},{"issue":"26","key":"2441_CR37","doi-asserted-by":"publisher","first-page":"40621","DOI":"10.18632\/oncotarget.9746","volume":"7","author":"H Wu","year":"2016","unstructured":"Wu H, Ying M, Hu X (2016) Lactic acidosis switches cancer cells from aerobic glycolysis back to dominant oxidative phosphorylation. Oncotarget 7(26):40621\u201340633. https:\/\/doi.org\/10.18632\/oncotarget.9746","journal-title":"Oncotarget"}],"container-title":["Journal of Mathematical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00285-026-02441-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00285-026-02441-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00285-026-02441-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:40:42Z","timestamp":1789652442000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00285-026-02441-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":37,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["2441"],"URL":"https:\/\/doi.org\/10.1007\/s00285-026-02441-y","relation":{},"ISSN":["0303-6812","1432-1416"],"issn-type":[{"value":"0303-6812","type":"print"},{"value":"1432-1416","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]},"assertion":[{"value":"28 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 May 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable. The present study is a theoretical and computational investigation and does not involve human participants, animal subjects, patient-derived samples, or any identifiable or non-identifiable clinical data. Model structure, parameter ranges, and validation were based solely on previously published open-source studies. Therefore, ethical approval and informed consent were not required.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"34"}}