Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells
Mitochondrial dysfunction plays a primary role in neurodevelopmental anomalies and neurodegeneration of Down syndrome (DS) subjects. For this reason, targeting mitochondrial key genes, such as PGC-1α/PPARGC1A, is emerging as a good therapeutic approach to attenuate cognitive disability in DS. After...
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Frontiers Media S.A.
2019-06-01
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Series: | Frontiers in Genetics |
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Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00606/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nunzia Mollo Maria Nitti Maria Nitti Lucrezia Zerillo Deriggio Faicchia Teresa Micillo Rossella Accarino Agnese Secondo Tiziana Petrozziello Gaetano Calì Rita Cicatiello Ferdinando Bonfiglio Viviana Sarnataro Rita Genesio Antonella Izzo Paolo Pinton Giuseppe Matarese Giuseppe Matarese Simona Paladino Anna Conti Lucio Nitsch Lucio Nitsch |
spellingShingle |
Nunzia Mollo Maria Nitti Maria Nitti Lucrezia Zerillo Deriggio Faicchia Teresa Micillo Rossella Accarino Agnese Secondo Tiziana Petrozziello Gaetano Calì Rita Cicatiello Ferdinando Bonfiglio Viviana Sarnataro Rita Genesio Antonella Izzo Paolo Pinton Giuseppe Matarese Giuseppe Matarese Simona Paladino Anna Conti Lucio Nitsch Lucio Nitsch Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells Frontiers in Genetics Down syndrome/therapy pioglitazone energy metabolism oxidative stress mitochondrial dysfunction mitochondrial dynamics |
author_facet |
Nunzia Mollo Maria Nitti Maria Nitti Lucrezia Zerillo Deriggio Faicchia Teresa Micillo Rossella Accarino Agnese Secondo Tiziana Petrozziello Gaetano Calì Rita Cicatiello Ferdinando Bonfiglio Viviana Sarnataro Rita Genesio Antonella Izzo Paolo Pinton Giuseppe Matarese Giuseppe Matarese Simona Paladino Anna Conti Lucio Nitsch Lucio Nitsch |
author_sort |
Nunzia Mollo |
title |
Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells |
title_short |
Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells |
title_full |
Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells |
title_fullStr |
Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells |
title_full_unstemmed |
Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells |
title_sort |
pioglitazone improves mitochondrial organization and bioenergetics in down syndrome cells |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2019-06-01 |
description |
Mitochondrial dysfunction plays a primary role in neurodevelopmental anomalies and neurodegeneration of Down syndrome (DS) subjects. For this reason, targeting mitochondrial key genes, such as PGC-1α/PPARGC1A, is emerging as a good therapeutic approach to attenuate cognitive disability in DS. After demonstrating the efficacy of the biguanide metformin (a PGC-1α activator) in a cell model of DS, we extended the study to other molecules that regulate the PGC-1α pathway acting on PPAR genes. We, therefore, treated trisomic fetal fibroblasts with different doses of pioglitazone (PGZ) and evaluated the effects on mitochondrial dynamics and function. Treatment with PGZ significantly increased mRNA and protein levels of PGC-1α. Mitochondrial network was fully restored by PGZ administration affecting the fission-fusion mitochondrial machinery. Specifically, optic atrophy 1 (OPA1) and mitofusin 1 (MFN1) were upregulated while dynamin-related protein 1 (DRP1) was downregulated. These effects, together with a significant increase of basal ATP content and oxygen consumption rate, and a significant decrease of reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in trisomic cells. In conclusion, we demonstrate that PGZ is able to improve mitochondrial phenotype even at low concentrations (0.5 μM). We also speculate that a combination of drugs that target mitochondrial function might be advantageous, offering potentially higher efficacy and lower individual drug dosage. |
topic |
Down syndrome/therapy pioglitazone energy metabolism oxidative stress mitochondrial dysfunction mitochondrial dynamics |
url |
https://www.frontiersin.org/article/10.3389/fgene.2019.00606/full |
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doaj-8a750e35c731476aaf9c71b295b4d1b32020-11-25T03:49:22ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-06-011010.3389/fgene.2019.00606460022Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome CellsNunzia Mollo0Maria Nitti1Maria Nitti2Lucrezia Zerillo3Deriggio Faicchia4Teresa Micillo5Rossella Accarino6Agnese Secondo7Tiziana Petrozziello8Gaetano Calì9Rita Cicatiello10Ferdinando Bonfiglio11Viviana Sarnataro12Rita Genesio13Antonella Izzo14Paolo Pinton15Giuseppe Matarese16Giuseppe Matarese17Simona Paladino18Anna Conti19Lucio Nitsch20Lucio Nitsch21Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyInstitute of Experimental Endocrinology and Oncology, National Research Council, Naples, ItalyDepartment of Biology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, ItalyDepartment of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, ItalyInstitute of Experimental Endocrinology and Oncology, National Research Council, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Biomedicine, University of Basel, Basel, SwitzerlandDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyInstitute of Experimental Endocrinology and Oncology, National Research Council, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyInstitute of Experimental Endocrinology and Oncology, National Research Council, Naples, ItalyMitochondrial dysfunction plays a primary role in neurodevelopmental anomalies and neurodegeneration of Down syndrome (DS) subjects. For this reason, targeting mitochondrial key genes, such as PGC-1α/PPARGC1A, is emerging as a good therapeutic approach to attenuate cognitive disability in DS. After demonstrating the efficacy of the biguanide metformin (a PGC-1α activator) in a cell model of DS, we extended the study to other molecules that regulate the PGC-1α pathway acting on PPAR genes. We, therefore, treated trisomic fetal fibroblasts with different doses of pioglitazone (PGZ) and evaluated the effects on mitochondrial dynamics and function. Treatment with PGZ significantly increased mRNA and protein levels of PGC-1α. Mitochondrial network was fully restored by PGZ administration affecting the fission-fusion mitochondrial machinery. Specifically, optic atrophy 1 (OPA1) and mitofusin 1 (MFN1) were upregulated while dynamin-related protein 1 (DRP1) was downregulated. These effects, together with a significant increase of basal ATP content and oxygen consumption rate, and a significant decrease of reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in trisomic cells. In conclusion, we demonstrate that PGZ is able to improve mitochondrial phenotype even at low concentrations (0.5 μM). We also speculate that a combination of drugs that target mitochondrial function might be advantageous, offering potentially higher efficacy and lower individual drug dosage.https://www.frontiersin.org/article/10.3389/fgene.2019.00606/fullDown syndrome/therapypioglitazoneenergy metabolismoxidative stressmitochondrial dysfunctionmitochondrial dynamics |