Inhibition of Drp1-mediated mitochondrial fission improves mitochondrial dynamics and bioenergetics stimulating neurogenesis in hippocampal progenitor cells from a Down syndrome mouse model
| Autor: | Domenico De Rasmo, Daniela Valenti, Leonardo Rossi, Anna Signorile, Francesco Bellomo, Domenico Marzulli, Rosa Anna Vacca |
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| Rok vydání: | 2017 |
| Předmět: |
Dynamins
0301 basic medicine Hippocampal neurogenesis Neurogenesis Down syndrome Drp1 Mitochondrion Biology Hippocampus Mitochondrial Dynamics GTP Phosphohydrolases Mice 03 medical and health sciences Mitofusin-2 Optic Atrophy Autosomal Dominant medicine Animals Molecular Biology Cell Proliferation Quinazolinones Genetics Mitochondrial network Neurodegeneration medicine.disease Mitochondria Cell biology Disease Models Animal 030104 developmental biology mitochondrial fusion Mdivi-1 DNAJA3 Molecular Medicine Optic Atrophy 1 Mitochondrial fission Energy Metabolism Mitochondrial dysfunction |
| Zdroj: | Biochimica et biophysica acta. Molecular basis of disease 1863 (2017): 3117–3127. doi:10.1016/j.bbadis.2017.09.014 info:cnr-pdr/source/autori:Valenti, Daniela; Rossi, Leonardo; Marzulli, Domenico; Bellomo, Francesco; De Rasmo, Domenico; Signorile, Anna; Vacca, Rosa Anna/titolo:Inhibition of Drp1-mediated mitochondrial fission improves mitochondrial dynamics and bioenergetics stimulating neurogenesis in hippocampal progenitor cells from a Down syndrome mouse model/doi:10.1016%2Fj.bbadis.2017.09.014/rivista:Biochimica et biophysica acta. Molecular basis of disease/anno:2017/pagina_da:3117/pagina_a:3127/intervallo_pagine:3117–3127/volume:1863 |
| ISSN: | 0925-4439 |
| Popis: | Functional and structural damages to mitochondria have been critically associated with the pathogenesis of Down syndrome (DS), a human multifactorial disease caused by trisomy of chromosome 21 and associated with neurodevelopmental delay, intellectual disability and early neurodegeneration. Recently, we demonstrated in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice -a widely used model of DS - a severe impairment of mitochondrial bioenergetics and biogenesis and reduced NPC proliferation. Here we further investigated the origin of mitochondrial dysfunction in DS and explored a possible mechanistic link among alteration of mitochondrial dynamics, mitochondrial dysfunctions and defective neurogenesis in DS. We first analyzed mitochondrial network and structure by both confocal and transmission electron microscopy as well as by evaluating the levels of key proteins involved in the fission and fusion machinery. We found a fragmentation of mitochondria due to an increase in mitochondrial fission associated with an up-regulation of dynamin-related protein 1 (Drp1), and a decrease in mitochondrial fusion associated with a down-regulation of mitofusin 2 (Mnf2) and increased proteolysis of optic atrophy 1 (Opa1). Next, using the well-known neuroprotective agent mitochondrial division inhibitor 1 (Mdivi-1), we assessed whether the inhibition of mitochondrial fission might reverse alteration of mitochondrial dynamics and mitochondrial dysfunctions in DS neural progenitors cells. We demonstrate here for the first time, that Mdivi-1 restores mitochondrial network organization, mitochondrial energy production and ultimately improves proliferation and neuronal differentiation of NPCs. This research paves the way for the discovery of new therapeutic tools in managing some DS-associated clinical manifestations. |
| Databáze: | OpenAIRE |
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