{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:06:01Z","timestamp":1788066361241,"version":"build-2784847793"},"reference-count":53,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ICARE-Europe research","award":["RM12117A86C9B00F"],"award-info":[{"award-number":["RM12117A86C9B00F"]}]},{"name":"ICARE-Europe research","award":["RM11916B85524428"],"award-info":[{"award-number":["RM11916B85524428"]}]},{"name":"Lazio-Innova","award":["RM12117A86C9B00F"],"award-info":[{"award-number":["RM12117A86C9B00F"]}]},{"name":"Lazio-Innova","award":["RM11916B85524428"],"award-info":[{"award-number":["RM11916B85524428"]}]},{"name":"IBPM","award":["RM12117A86C9B00F"],"award-info":[{"award-number":["RM12117A86C9B00F"]}]},{"name":"IBPM","award":["RM11916B85524428"],"award-info":[{"award-number":["RM11916B85524428"]}]},{"name":"University of Sapienza fund","award":["RM12117A86C9B00F"],"award-info":[{"award-number":["RM12117A86C9B00F"]}]},{"name":"University of Sapienza fund","award":["RM11916B85524428"],"award-info":[{"award-number":["RM11916B85524428"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>KAT Gcn5 and DUB Ubp8 are required for respiration and mitochondria functions in budding yeast, and in this study we show that loss of respiratory activity is acquired over time. Interestingly, we show that absence of Ubp8 allows cells to grow in hypoxic conditions with altered mitophagy. Comparatively, the aggressive glioblastoma (GBM) multiforme tumor shows survival mechanisms able to overcome hypoxia in the brain. Starting from yeast and our findings on the role of Ubp8 in hypoxia, we extended our analysis to the human ortholog and signature cancer gene Usp22 in glioblastoma tumor specimens. Here we demonstrate that Usp22 is localized and overexpressed in the pseudo-palisade tissue around the necrotic area of the tumor. In addition, Usp22 colocalizes with the mitophagy marker Parkin, indicating a link with mitochondria function in GBM. Collectively, this evidence suggests that altered expression of Usp22 might provide a way for tumor cells to survive in hypoxic conditions, allowing the escape of cells from the necrotic area toward vascularized tissues. Collectively, our experimental data suggest a model for a possible mechanism of uncontrolled proliferation and invasion in glioblastoma.<\/jats:p>","DOI":"10.3390\/cells11101682","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T12:25:57Z","timestamp":1652963157000},"page":"1682","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of yUbp8 in Mitochondria and Hypoxia Entangles the Finding of Human Ortholog Usp22 in the Glioblastoma Pseudo-Palisade Microlayer"],"prefix":"10.3390","volume":"11","author":[{"given":"Veronica","family":"De Luca","sequence":"first","affiliation":[{"name":"Department of Biology and Biotechnologies \u201cCharles Darwin\u201d, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies \u201cCharles Darwin\u201d, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Cretella","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies \u201cCharles Darwin\u201d, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Montanari","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies \u201cCharles Darwin\u201d, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Saliola","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies \u201cCharles Darwin\u201d, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4962-4343","authenticated-orcid":false,"given":"Gabriele","family":"Ciaffi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sant\u2019 Andrea Hospital, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-6856","authenticated-orcid":false,"given":"Andrea","family":"Vecchione","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sant\u2019 Andrea Hospital, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Stoppacciaro","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sant\u2019 Andrea Hospital, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9459-7490","authenticated-orcid":false,"given":"Patrizia","family":"Filetici","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology\u2014CNR, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.bbabio.2004.09.005","article-title":"The epidemiology of mitochondrial disorders\u2014Past, present and future","volume":"1659","author":"Schaefer","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0014-5793(98)01467-7","article-title":"The complete sequence of the mitochondrial genome of Saccharomyces cerevisiae","volume":"440","author":"Foury","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a004440","DOI":"10.1101\/cshperspect.a004440","article-title":"Aging as an event of proteostasis collapse","volume":"3","author":"Taylor","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1007\/s004380051156","article-title":"Alpha and beta subunits of F1-ATPase are required for survival of petite mutants in Saccharomyces cerevisiae","volume":"262","author":"Chen","year":"1999","journal-title":"Mol. Gen. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1006\/jmbi.1996.0048","article-title":"Structural analysis of mitochondrial DNA molecules from fungi and plants using moving pictures and pulsed-field gel electrophoresis","volume":"255","author":"Bendich","year":"1996","journal-title":"J. Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21649","DOI":"10.1074\/jbc.M803236200","article-title":"The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex","volume":"283","author":"Drose","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/febs.13778","article-title":"Ground control to major TOM: Mitochondria-nucleus communication","volume":"284","author":"Schuldiner","year":"2017","journal-title":"FEBS J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/embor.2013.40","article-title":"Phosphorylation of mitophagy and pexophagy receptors coordinates their interaction with Atg8 and Atg11","volume":"14","author":"Farre","year":"2013","journal-title":"EMBO Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1101\/gad.11.13.1640","article-title":"Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: Characterization of an Ada complex and the SAGA (Spt\/Ada) complex","volume":"11","author":"Grant","year":"1997","journal-title":"Genes Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s10522-004-2568-x","article-title":"The histone acetyltransferase GCN5 modulates the retrograde response and genome stability determining yeast longevity","volume":"5","author":"Kim","year":"2004","journal-title":"Biogerontology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1089\/rej.2005.8.3","article-title":"Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging","volume":"8","author":"Lemasters","year":"2005","journal-title":"Rejuvenation Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R170","DOI":"10.1016\/j.cub.2018.01.004","article-title":"Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance","volume":"28","author":"Pickles","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/sj.emboj.7601972","article-title":"Quality control of mitochondria: Protection against neurodegeneration and ageing","volume":"27","author":"Tatsuta","year":"2008","journal-title":"EMBO J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1111\/j.1567-1364.2010.00659.x","article-title":"Mitophagy in yeast: Actors and physiological roles","volume":"10","author":"Camougrand","year":"2010","journal-title":"FEMS Yeast Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.15252\/embj.201796697","article-title":"Molecular definitions of autophagy and related processes","volume":"36","author":"Galluzzi","year":"2017","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.devcel.2009.06.014","article-title":"Atg32 is a mitochondrial protein that confers selectivity during mitophagy","volume":"17","author":"Kanki","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1083\/jcb.200809125","article-title":"Parkin is recruited selectively to impaired mitochondria and promotes their autophagy","volume":"183","author":"Narendra","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1038\/emboj.2011.104","article-title":"Mitochondria regulate autophagy by conserved signalling pathways","volume":"30","author":"Graef","year":"2011","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1038\/sj.cdd.4401697","article-title":"Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast","volume":"12","author":"Priault","year":"2005","journal-title":"Cell Death Differ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.tibs.2019.08.002","article-title":"Post-translational Modifications of Key Machinery in the Control of Mitophagy","volume":"45","author":"Wang","year":"2020","journal-title":"Trends Biochem. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0014-5793(03)00801-9","article-title":"The yeast deubiquitinating enzyme Ubp16 is anchored to the outer mitochondrial membrane","volume":"549","author":"Kinner","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.celrep.2015.01.044","article-title":"Synthetic quantitative array technology identifies the Ubp3-Bre5 deubiquitinase complex as a negative regulator of mitophagy","volume":"10","author":"Muller","year":"2015","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1159\/000134324","article-title":"Isolation and characterization of a human cDNA clone (GCN5L1) homologous to GCN5, a yeast transcription activator","volume":"73","author":"Inoue","year":"1996","journal-title":"Cytogenet Cell Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.tcb.2018.01.007","article-title":"GCN5L1\/BLOS1 Links Acetylation, Organelle Remodeling, and Metabolism","volume":"28","author":"Scott","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1074\/jbc.M113.521641","article-title":"GCN5-like protein 1 (GCN5L1) controls mitochondrial content through coordinated regulation of mitochondrial biogenesis and mitophagy","volume":"289","author":"Scott","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1042\/BJ20120118","article-title":"Identification of a molecular component of the mitochondrial acetyltransferase programme: A novel role for GCN5L1","volume":"443","author":"Scott","year":"2012","journal-title":"Biochem. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17676","DOI":"10.1074\/jbc.AC118.005462","article-title":"The protein acetylase GCN5L1 modulates hepatic fatty acid oxidation activity via acetylation of the mitochondrial beta-oxidation enzyme HADHA","volume":"293","author":"Thapa","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1016\/j.bbamcr.2016.10.002","article-title":"SAGA complex and Gcn5 are necessary for respiration in budding yeast","volume":"1863","author":"Canzonetta","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/j.bbamcr.2018.07.025","article-title":"Ubiquitin protease Ubp8 is necessary for S. cerevisiae respiration","volume":"1865","author":"Leo","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"bio041244","DOI":"10.1242\/bio.041244","article-title":"Gcn5 histone acetyltransferase is present in the mitoplasts","volume":"8","author":"Montanari","year":"2019","journal-title":"Biol. Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.trecan.2015.10.009","article-title":"Glioblastoma: Defining Tumor Niches","volume":"1","author":"Hambardzumyan","year":"2015","journal-title":"Trends Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4860","DOI":"10.7150\/thno.35882","article-title":"HIF-1alpha\/Wnt signaling-dependent control of gene transcription regulates neuronal differentiation of glioblastoma stem cells","volume":"9","author":"Boso","year":"2019","journal-title":"Theranostics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ccr.2009.03.018","article-title":"Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells","volume":"15","author":"Li","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41467-018-03050-0","article-title":"Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2alpha","volume":"9","author":"Wang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"659","DOI":"10.7326\/0003-4819-138-8-200304150-00014","article-title":"Malignant glioma physiology: Cellular response to hypoxia and its role in tumor progression","volume":"138","author":"Brat","year":"2003","journal-title":"Ann. Intern. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1111\/cas.13646","article-title":"Ubiquitin-specific protease 22 acts as an oncoprotein to maintain glioma malignancy through deubiquitinating B cell-specific Moloney murine leukemia virus integration site 1 for stabilization","volume":"109","author":"Qiu","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/ncb3396","article-title":"Nuclear GSK3beta promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22","volume":"18","author":"Zhou","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.mito.2009.07.004","article-title":"Can yeast be used to study mitochondrial diseases? Biolistic tRNA mutants for the analysis of mechanisms and suppressors","volume":"9","author":"Zhou","year":"2009","journal-title":"Mitochondrion"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"205","DOI":"10.4161\/auto.5331","article-title":"Rosella: A fluorescent pH-biosensor for reporting vacuolar turnover of cytosol and organelles in yeast","volume":"4","author":"Rosado","year":"2008","journal-title":"Autophagy"},{"key":"ref_40","unstructured":"Louis, D.N.O.H., Wiestler, O.D., and Cavenee, W.K. (2016). WHO Classification of Tumours of the Central Nervous System, International Agency for Research on Cancer. [4th ed.]."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.isci.2018.12.021","article-title":"Srv2 Is a Pro-fission Factor that Modulates Yeast Mitochondrial Morphology and Respiration by Regulating Actin Assembly","volume":"11","author":"Chen","year":"2019","journal-title":"iScience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/1097-0061(200011)16:15<1421::AID-YEA624>3.0.CO;2-U","article-title":"Mitochondria-targeted green fluorescent proteins: Convenient tools for the study of organelle biogenesis in Saccharomyces cerevisiae","volume":"16","author":"Westermann","year":"2000","journal-title":"Yeast"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/BF00413308","article-title":"Fine structure of OXI1, the mitochondrial gene coding for subunit II of yeast cytochrome c oxidase","volume":"1","author":"Guba","year":"1979","journal-title":"Curr. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Torggler, R., Papinski, D., and Kraft, C. (2017). Assays to Monitor Autophagy in Saccharomyces cerevisiae. Cells, 6.","DOI":"10.3390\/cells6030023"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17593","DOI":"10.1074\/jbc.RA118.005410","article-title":"Porin proteins have critical functions in mitochondrial phospholipid metabolism in yeast","volume":"293","author":"Miyata","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1083\/jcb.201601082","article-title":"Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria","volume":"214","author":"Miyata","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e01504-20","DOI":"10.1128\/mBio.01504-20","article-title":"Gcn5p and Ubp8p Affect Protein Ubiquitylation and Cell Proliferation by Altering the Fermentative\/Respiratory Flux Balance in Saccharomyces cerevisiae","volume":"11","author":"Fanelli","year":"2020","journal-title":"mBio"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13024-020-00367-7","article-title":"PINK1 and Parkin mitochondrial quality control: A source of regional vulnerability in Parkinson\u2019s disease","volume":"15","author":"Ge","year":"2020","journal-title":"Mol. Neuro."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/mds.27193","article-title":"Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature","volume":"32","author":"Schneider","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ceb.2010.03.005","article-title":"Multiple faces of the SAGA complex","volume":"22","author":"Koutelou","year":"2010","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrc704","article-title":"Hypoxia\u2014A key regulatory factor in tumour growth","volume":"2","author":"Harris","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.3389\/fphar.2018.01349","article-title":"Epigenetic Factors and Mitochondrial Biology in Yeast: A New Paradigm for the Study of Cancer Metabolism?","volume":"9","author":"Stoppacciaro","year":"2018","journal-title":"Front. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.4161\/cc.4.9.2001","article-title":"Death-from-cancer signatures and stem cell contribution to metastatic cancer","volume":"4","author":"Glinsky","year":"2005","journal-title":"Cell Cycle"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/10\/1682\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:14:36Z","timestamp":1760138076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/10\/1682"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,19]]},"references-count":53,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cells11101682"],"URL":"https:\/\/doi.org\/10.3390\/cells11101682","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,19]]}}}