{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:25:01Z","timestamp":1760059501114,"version":"build-2065373602"},"reference-count":95,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto the Salud Carlos III","award":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"],"award-info":[{"award-number":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"]}]},{"name":"European Regional Development Fund (ERDF)","award":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"],"award-info":[{"award-number":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"]}]},{"name":"Fundaci\u00f3n Bancaria Unicaja","award":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"],"award-info":[{"award-number":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"]}]},{"name":"Valencian Council for Education, Culture, University, and Employment","award":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"],"award-info":[{"award-number":["FIS PI19\/00377 (2019)","FIS PI22\/00142 (2022)","CTS-5725","PY18-850","UPO-FEDER 2018 (UPO-1380614)","29015 M\u00e1laga","CIPROM\/2023\/053"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H2S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H2S and protein persulfidation, mitochondrial dysfunction, iron\/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants.<\/jats:p>","DOI":"10.3390\/antiox14060741","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T14:03:11Z","timestamp":1750082591000},"page":"741","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy"],"prefix":"10.3390","volume":"14","author":[{"given":"Jos\u00e9 Manuel","family":"Romero-Dom\u00ednguez","sequence":"first","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5209-370X","authenticated-orcid":false,"given":"Paula","family":"Cilleros-Holgado","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"G\u00f3mez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roc\u00edo","family":"Pi\u00f1ero-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Reche-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Romero-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nica","family":"\u00c1lvarez-C\u00f3rdoba","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5906-1662","authenticated-orcid":false,"given":"Alejandra","family":"L\u00f3pez-Cabrera","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta Castro","family":"De Oliveira","sequence":"additional","affiliation":[{"name":"Neuropediatria, Neurolinkia, C. Jard\u00edn de la Isla, 8, Local 4 y 5, 41014 Sevilla, Spain"},{"name":"FEA Pediatr\u00eda, Centro Universitario Hospitalar de Faro, R. Le\u00e3o Penedo, 8000-386 Faro, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s","family":"Rodr\u00edguez-Sacrist\u00e1n","sequence":"additional","affiliation":[{"name":"Neuropediatr\u00eda, Servicio de Pediatr\u00eda, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain"},{"name":"Departamento de Farmacolog\u00eda, Radiolog\u00eda y Pediatr\u00eda de la Facultad de Medicina de la Universidad de Sevilla, 41009 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1531-550X","authenticated-orcid":false,"given":"Susana","family":"Gonz\u00e1lez-Granero","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-6499","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Garc\u00eda-Verdugo","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4915-170X","authenticated-orcid":false,"given":"Angeles","family":"Aroca","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica Vegetal y Fotoss\u00edntesis, Consejo Superior de Investigaciones Cient\u00edficas, Universidad de Sevilla, 41092 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9705-1469","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"S\u00e1nchez-Alc\u00e1zar","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1136\/jmg.2005.036210","article-title":"ETHE1 mutations are specific to ethylmalonic encephalopathy","volume":"43","author":"Tiranti","year":"2006","journal-title":"J. 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