{
  "abstract": "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-mitophagy-lysosome 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-mitophagy 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-lysosome 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.",
  "abstract_shown": true,
  "affiliations": [
    "Dept. of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.",
    "Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia \"G. Salvatore\" (IEOMI), National Research Council (CNR), Naples, Italy.",
    "Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, Italy.",
    "Dept. of Translational Medicine, Medical Genetics, Federico II University, Naples, Italy.",
    "Dept. of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy. antonella.izzo@unina.it."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Nunzia Mollo"
    },
    {
      "affs": [
        0
      ],
      "name": "Rosalba Natale"
    },
    {
      "affs": [
        0
      ],
      "name": "Morena D'Ariano"
    },
    {
      "affs": [
        0
      ],
      "name": "Simona Coppola"
    },
    {
      "affs": [
        0
      ],
      "name": "Daniele Di Meglio"
    },
    {
      "affs": [
        0
      ],
      "name": "Adriana Limone"
    },
    {
      "affs": [
        1
      ],
      "name": "Gaetano Calì"
    },
    {
      "affs": [
        2
      ],
      "name": "Claudia D'Agostino"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Nunzia Pastore"
    },
    {
      "affs": [
        0
      ],
      "name": "Daniela Sarnataro"
    },
    {
      "affs": [
        0
      ],
      "name": "Simona Paladino"
    },
    {
      "affs": [
        0
      ],
      "name": "Anna Conti"
    },
    {
      "affs": [
        0
      ],
      "name": "Lucio Nitsch"
    },
    {
      "affs": [
        4
      ],
      "name": "Antonella Izzo",
      "orcid": "0000-0002-2672-4803"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8wman2j3fz4q5.bib",
  "cited_by": 0,
  "doi": "10.1007/s00018-026-06355-2",
  "fulltext_url": "https://europepmc.org/articles/PMC13683296",
  "id": "8wman2j3fz4q5",
  "issns": [
    "1420-682X",
    "1420-9071"
  ],
  "landing_url": "https://europepmc.org/article/MED/42900242",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "lcc",
      "QR1-502"
    ],
    [
      "openalex",
      "2713|Autophagy in Disease and Therapy"
    ]
  ],
  "openalex": "W7170036702",
  "pdf_url": "https://europepmc.org/articles/PMC13683296?pdf=render",
  "pmcid": "PMC13683296",
  "pmid": "42900242",
  "published": "2026-07-01",
  "publisher": "Springer",
  "ris": "https://research.draconitic.com/paper/8wman2j3fz4q5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:42Z",
      "native_id": "MED:42900242",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42900242"
    },
    {
      "first_seen": "2026-10-30T13:45:50Z",
      "native_id": "e4b86192685c4e05b65e924a22c4aa8e",
      "source": "doaj",
      "url": "https://doi.org/10.1007/s00018-026-06355-2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2713|Autophagy in Disease and Therapy",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts.",
  "title_text": "Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:45:50Z",
  "url": "https://research.draconitic.com/paper/8wman2j3fz4q5",
  "venue": "Cellular and molecular life sciences : CMLS",
  "versions": []
}