Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells.

Nunzia Mollo,Giuseppe Matarese,Ferdinando Bonfiglio,Gaetano Calì,Tiziana Petrozziello,Antonella Izzo,Lucio Nitsch,Rita Cicatiello,Rossella Accarino,Rita Genesio,Deriggio Faicchia,Simona Paladino,Maria Nitti,Agnese Secondo,Teresa Micillo,Lucrezia Zerillo,Viviana Sarnataro,Paolo Pinton,Anna Conti

doi:10.3389/fgene.2019.00606

Abstract

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.

Highlights

Over the last years, several drugs and nutraceuticals have been tested, mostly in the Ts65Dn mouse model of Down syndrome (DS), aimed at rescuing or attenuating deficits in learning and memory
Among the molecular mechanisms responsible for mitochondrial dysfunction in DS, we found that the dosage-related over-expression of a corepressor mapping to the chromosome 21 (Hsa21), namely NRIP1, inhibits the activity of the transcriptional activator PGC-1α (Izzo et al, 2014), a gene that orchestrates mitochondrial biogenesis and function (Scarpulla et al, 2012)
We found that the percentage of dead cells for each condition was around 2% in PGZ treated trisomic cells and controls, indicating that PGZ does not induce cellular death (Figure S1B)

Summary

Introduction

Several drugs and nutraceuticals have been tested, mostly in the Ts65Dn mouse model of Down syndrome (DS), aimed at rescuing or attenuating deficits in learning and memory. More than 20 molecules have been successfully identified to restore hippocampal deficits in adult mice (Gardiner, 2015) The results of these preclinical trials suggest that the amelioration or prevention of cognitive deficits in people with DS may be possible, paving the way to clinical trials many of Pioglitazone Effects in DS Mitochondria which are still in progress. Several studies demonstrated that mitochondrial dysfunction plays an important primary role in both altered neurodevelopment and neurodegeneration (Khacho and Slack, 2018)

Methods

Results

Conclusion