{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T22:05:32Z","timestamp":1776377132545,"version":"3.51.2"},"reference-count":58,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014Next Generation EU\u2014PNRR M6C2 (National Recovery and Resilience Plan)\u2014Investment 2.1 Enhancement and strengthening of biomedical research in the National Health Service","award":["PNRR-MR1-2022-1237634"],"award-info":[{"award-number":["PNRR-MR1-2022-1237634"]}]},{"name":"Serenella Servidei and Guido Primiano are members of the European Reference Network for Neuromuscular Diseases\u2014Project","award":["870177"],"award-info":[{"award-number":["870177"]}]},{"name":"Giuseppe Zampino e Chiara Leoni are members of the European Reference Networks on Rare Bone Diseases (ERN BOND) and Intellectual Disability, TeleHealth, Autism, and Congenital Anomalies"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Advances in next-generation sequencing have significantly improved the molecular diagnosis of mitochondrial diseases (MDs), a group of heterogeneous neurogenetic disorders. However, progress in understanding their pathogenic mechanisms and translating this knowledge into effective therapies remains limited. Elucidating the molecular determinants of phenotypic variability in primary MDs is essential to uncover disease mechanisms and identify novel therapeutic targets. We investigated a cohort of eight adult patients with genetically confirmed Progressive External Ophthalmoplegia (PEO)\u2014an extremely rare mitochondrial disorder\u2014and compared them with eight age- and sex-matched healthy controls. A comprehensive multi-omics approach combining LC\u2013MS\/MS-based proteomics, UPLC\u2013MS\/MS-based metabolomics, ATR\u2013FTIR spectroscopy, and chemometric multivariate analysis was employed to identify molecular alterations associated with mitochondrial dysfunction. Distinct proteomic and metabolic patterns related to energy metabolism were observed in PEO patients, correlating with their genetic background. Metabolomic analysis showed altered amino acid levels (seven statistically relevant) and disruptions in the metabolism of cysteine, methionine, and glutathione; proteomics finding (154 differentially expressed proteins) revealed dysregulation in extracellular matrix (ECM) organization and immune response pathways. This integrative analytical strategy offers new insights into the molecular complexity of PEO and mitochondrial disorders. The identification of disease-associated molecular signatures may enhance the understanding of pathogenic mechanisms and support the development of improved diagnostic and therapeutic approaches for MDs.<\/jats:p>","DOI":"10.3390\/ijms262311257","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T15:33:06Z","timestamp":1763739186000},"page":"11257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Urinary Multi-Omics Profiling Reveals Systemic Molecular Alterations in Progressive External Ophthalmoplegia"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8975-4947","authenticated-orcid":false,"given":"Michela","family":"Cicchinelli","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Biotecnologiche di Base Cliniche Intensivologiche e Perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-7008","authenticated-orcid":false,"given":"Guido","family":"Primiano","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"},{"name":"Dipartimento di Neuroscienze, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4673-4519","authenticated-orcid":false,"given":"Francesca","family":"Canu","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biotecnologiche di Base Cliniche Intensivologiche e Perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3600-392X","authenticated-orcid":false,"given":"Jacopo","family":"Gervasoni","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9415-9175","authenticated-orcid":false,"given":"Aniello","family":"Primiano","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7448-0604","authenticated-orcid":false,"given":"Lavinia","family":"Santucci","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4293-1540","authenticated-orcid":false,"given":"Anna","family":"Percio","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biotecnologiche di Base Cliniche Intensivologiche e Perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4521-0020","authenticated-orcid":false,"given":"Viviana","family":"Greco","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biotecnologiche di Base Cliniche Intensivologiche e Perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4089-637X","authenticated-orcid":false,"given":"Chiara","family":"Leoni","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Sabino","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelangelo","family":"Ardito","sequence":"additional","affiliation":[{"name":"Dipartimento di Neuroscienze, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2661-4831","authenticated-orcid":false,"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"},{"name":"Dipartimento di Scienze della Vita e Sanit\u00e0 Pubblica, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8478-2799","authenticated-orcid":false,"given":"Serenella","family":"Servidei","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u2018Agostino Gemelli\u2019 IRCCS, 00168 Rome, Italy"},{"name":"Dipartimento di Neuroscienze, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, 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