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Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mitochondrial dysfunction is a core cellular abnormality in Down syndrome (DS), yet the mechanisms underlying impaired mitochondrial quality control remain poorly defined. Here, we provide an integrated characterization of the autophagy\u2013mitophagy\u2013lysosome axis in human trisomic fetal fibroblasts (DS-HFFs). We show that trisomic cells display a paradoxical combination of elevated basal autophagy\/mitophagy-related markers and defective mitochondrial clearance, indicative of a saturated and inefficient quality control system. DS-HFFs exhibit increased steady-state levels of PINK1, PARKIN, OPTN, NDP52, LC3-II, and p62, accumulation of autophagic vacuoles, reduced autophagic flux, and impaired delivery of mitochondria to lysosomes. We further demonstrate that metformin alleviates the saturation of the autophagy\u2013mitophagy pathway by modulating multiple components of the mitochondrial quality control pathway, including attenuation of mTOR-associated signaling, enhancement of autophagic flux and normalization of mitophagy-related protein levels. Crucially, metformin increases mitochondria\u2013lysosome association and rescues lysosomal degradative competence as shown by increased Dq-BSA activity, and increased maturation of Cathepsin D. Together, our findings support mitophagy inefficiency due to pathway saturation as a key pathogenetic mechanism in trisomic cells and identify metformin as a pharmacological tool capable of relieving the proteostatic overload intrinsic to trisomy 21. More broadly, these results align with a model in which aneuploidy imposes a chronic proteostatic burden that compromises organelle quality control.<\/jats:p>","DOI":"10.1007\/s00018-026-06355-2","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T08:14:34Z","timestamp":1784708074000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts"],"prefix":"10.1007","volume":"83","author":[{"given":"Nunzia","family":"Mollo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalba","family":"Natale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morena","family":"D\u2019Ariano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Coppola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Di Meglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Limone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Cal\u00ec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"D\u2019Agostino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzia","family":"Pastore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Sarnataro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Paladino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Conti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Nitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2672-4803","authenticated-orcid":false,"given":"Antonella","family":"Izzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"6355_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/S41572-019-0143-7","author":"SE Antonarakis","year":"2020","unstructured":"Antonarakis SE, Skotko BG, Rafii MS et al (2020) Down syndrome. 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