Corrigendum: Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells.

[This corrects the article DOI: 10.3389/fgene.2019.00606.].

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 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.

Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets.

Trisomy of chromosome 21 (TS21) is the most common autosomal aneuploidy compatible with postnatal survival with a prevalence of 1 in 700 newborns. Its phenotype is highly complex with constant features, such as mental retardation, dysmorphic traits and hypotonia, and variable features including heart defects, susceptibility to Alzheimer's disease (AD), type 2 diabetes, obesity and immune disorders. Overexpression of genes on chromosome-21 (Hsa21) is responsible for the pathogenesis of Down syndrome (DS) phenotypic features either in a direct or in an indirect manner since many Hsa21 genes can affect the expression of other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function and energy conversion, and play a central role in the mitochondrial dysfunction and chronic oxidative stress, consistently observed in DS subjects.Recent studies highlight the deep interconnections between mitochondrial dysfunction and DS phenotype. In this short review we first provide a basic overview of mitochondrial phenotype in DS cells and tissues. We then discuss how specific Hsa21 genes may be involved in determining the disruption of mitochondrial DS phenotype and biogenesis. Finally we briefly focus on drugs that affect mitochondrial function and mitochondrial network suggesting possible therapeutic approaches to improve and/or prevent some aspects of the DS phenotype.

Prenatally diagnosed distal 16p11.2 microdeletion with a novel association with congenital diaphragmatic hernia: a case report.

A prenatal case presenting with congenital diaphragmatic hernia (CDH) and distal 16p11.2 microdeletion suggests two possible causative hypotheses: (1) a functional effect of chromatin loopings between the distal and the proximal 16p11.2 microdeletion traits, associated with CHD; (2) a possible role of ATP2A1, a deleted gene involved in diaphragm development.