Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts.
5 affiliations
- 1Dept. of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
- 2Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia "G. Salvatore" (IEOMI), National Research Council (CNR), Naples, Italy.
- 3Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, Italy.
- 4Dept. of Translational Medicine, Medical Genetics, Federico II University, Naples, Italy.
- 5Dept. of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy. [email protected].
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.
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BibTeX
@article{mollo2026metformin,
title = {{Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts.}},
author = {Nunzia Mollo and Rosalba Natale and Morena D'Ariano and Simona Coppola and Daniele Di Meglio and Adriana Limone and Gaetano Calì and Claudia D'Agostino and Nunzia Pastore and Daniela Sarnataro and Simona Paladino and Anna Conti and Lucio Nitsch and Antonella Izzo},
journal = {Cellular and molecular life sciences : CMLS},
year = {2026},
month = jul,
doi = {10.1007/s00018-026-06355-2},
url = {https://europepmc.org/article/MED/42900242},
note = {CC BY},
}
RIS
TY - JOUR
TI - Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts.
AU - Nunzia Mollo
AU - Rosalba Natale
AU - Morena D'Ariano
AU - Simona Coppola
AU - Daniele Di Meglio
AU - Adriana Limone
AU - Gaetano Calì
AU - Claudia D'Agostino
AU - Nunzia Pastore
AU - Daniela Sarnataro
AU - Simona Paladino
AU - Anna Conti
AU - Lucio Nitsch
AU - Antonella Izzo
PY - 2026
DA - 2026/07/01
JO - Cellular and molecular life sciences : CMLS
DO - 10.1007/s00018-026-06355-2
UR - https://europepmc.org/article/MED/42900242
AB - 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.
SN - 1420-682X
SN - 1420-9071
ER -