title: Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells.
abstract: Alterations in mitochondrial activity and morphology have been demonstrated in human cells and tissues from individuals with Down syndrome (DS), as well as in DS mouse models. An impaired activity of the transcriptional coactivator PGC-1α/PPARGC1A due to the overexpression of chromosome 21 genes, such as NRIP1/RIP140, has emerged as an underlying cause of mitochondrial dysfunction in DS. We tested the hypothesis that the activation of the PGC-1α pathway might indeed reverse this mitochondrial dysfunction. To this end, we investigated the effects of metformin, a PGC-1α-activating drug, on mitochondrial morphology and function in DS foetal fibroblasts. Metformin induced both the expression of PGC-1α and an augmentation of its activity, as demonstrated by the increased expression of target genes, strongly promoting mitochondrial biogenesis. Furthermore, metformin enhanced oxygen consumption, ATP production, and overall mitochondrial activity. Most interestingly, this treatment reversed the fragmentation of mitochondria observed in DS and induced the formation of a mitochondrial network with a branched and elongated tubular morphology. Concomitantly, cristae remodelling occurred and the alterations observed by electron microscopy were significantly reduced. We finally demonstrated that the expression of genes of the fission/fusion machinery, namely OPA1 and MFN2, was reduced in trisomic cells and increased by metformin treatment. These results indicate that metformin promotes the formation of a mitochondrial network and corrects the mitochondrial dysfunction in DS cells. We speculate that alterations in the mitochondrial dynamics can be relevant in the pathogenesis of DS and that metformin can efficiently counteract these alterations, thus exerting protective effects against DS-associated pathologies.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Izzo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.|Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Nitti
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Mollo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Paladino
authors.affiliation: Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Procaccini
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Deriggio
authors.initials: D
authors.lastname: Faicchia
authors.affiliation: Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Calì
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Genesio
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Bonfiglio
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Cicatiello
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Polishchuk
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matarese
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Conti
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Nitsch
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000096:biosynthesis; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000255:Adenosine Triphosphate; D008687:Metformin; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; C498809:Opa1 protein, mouse