{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:54:06Z","timestamp":1792526046304,"version":"4.5.0"},"reference-count":61,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN (Progetti di Ricerca di Rilevante Interesse Nazionale \u2013 grant number Prot. 2017SNRXH3) to Prof. Margherita Ruoppolo","award":["Prot. 2017SNRXH3"],"award-info":[{"award-number":["Prot. 2017SNRXH3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Methylmalonic acidemia (MMA) is a rare inborn error of metabolism caused by deficiency of the methylmalonyl-CoA mutase (MUT) enzyme. Downstream MUT deficiency, methylmalonic acid accumulates together with toxic metabolites from propionyl-CoA and other compounds upstream of the block in the enzyme pathway. The presentation is with life-threatening acidosis, respiratory distress, brain disturbance, hyperammonemia, and ketosis. Survivors develop poorly understood multi-organ damage, notably to the brain and kidneys. The HEK 293 cell line was engineered by CRISPR\/Cas9 technology to knock out the MUT gene (MUT-KO). Shotgun label-free quantitative proteomics and bioinformatics analyses revealed potential damaging biological processes in MUT-deficient cells. MUT-KO induced alteration of cellular architecture and morphology, and ROS overproduction. We found the alteration of proteins involved in cytoskeleton and cell adhesion organization, cell trafficking, mitochondrial, and oxidative processes, as validated by the regulation of VIM, EXT2, SDC2, FN1, GLUL, and CHD1. Additionally, a cell model of MUT-rescuing was developed in order to control the specificity of MUT-KO effects. Globally, the proteomic landscape of MUT-KO suggests the cell model to have an increased susceptibility to propionate- and H2O2-induced stress through an impairment of the mitochondrial functionality and unbalances in the oxidation-reduction processes.<\/jats:p>","DOI":"10.3390\/ijms21144998","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T10:35:18Z","timestamp":1594809318000},"page":"4998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6386-2009","authenticated-orcid":false,"given":"Michele","family":"Costanzo","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy"},{"name":"CEINGE\u2014Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6035-8213","authenticated-orcid":false,"given":"Marianna","family":"Caterino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy"},{"name":"CEINGE\u2014Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1858-2833","authenticated-orcid":false,"given":"Armando","family":"Cevenini","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy"},{"name":"CEINGE\u2014Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0530-1737","authenticated-orcid":false,"given":"Vincent","family":"Jung","sequence":"additional","affiliation":[{"name":"Proteomics Platform Necker, Universit\u00e9 de Paris\u2014Structure F\u00e9d\u00e9rative de Recherche Necker, Inserm US24\/CNRS UMS3633, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cerina","family":"Chhuon","sequence":"additional","affiliation":[{"name":"Proteomics Platform Necker, Universit\u00e9 de Paris\u2014Structure F\u00e9d\u00e9rative de Recherche Necker, Inserm US24\/CNRS UMS3633, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Lipecka","sequence":"additional","affiliation":[{"name":"Proteomics Platform Necker, Universit\u00e9 de Paris\u2014Structure F\u00e9d\u00e9rative de Recherche Necker, Inserm US24\/CNRS UMS3633, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2024-9781","authenticated-orcid":false,"given":"Roberta","family":"Fedele","sequence":"additional","affiliation":[{"name":"CEINGE\u2014Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Chiara","family":"Guerrera","sequence":"additional","affiliation":[{"name":"Proteomics Platform Necker, Universit\u00e9 de Paris\u2014Structure F\u00e9d\u00e9rative de Recherche Necker, Inserm US24\/CNRS UMS3633, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-0602","authenticated-orcid":false,"given":"Margherita","family":"Ruoppolo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy"},{"name":"CEINGE\u2014Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ymgme.2005.07.020","article-title":"Genetic and genomic systems to study methylmalonic acidemia","volume":"86","author":"Chandler","year":"2005","journal-title":"Mol. 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