Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets

Antonella Izzo,Viviana Sarnataro,Lucio Nitsch,Maria Nitti,Simona Paladino,Ferdinando Bonfiglio,Rita Genesio,Maria Barbato,Gaetano Calì,Nunzia Mollo,Rita Cicatiello,Anna Conti

doi:10.1186/s10020-018-0004-y

Abstract

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.

Highlights

Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 (TS21) in which the specific phenotypic manifestations may result from the balance among genetic, environmental and stochastic events (Rachidi and Lopes 2007; Reeves et al 2001)
We have identified and validated SLC25A4/ANT1, a gene that plays a major role in mitochondrial function as it codes for the main translocator of ADP/ATP across the mitochondrial membrane (Izzo et al, 2017a)
Drugs capable of modulating the activity of PGC-1α and/or the downstream PPAR proteins have been available for a long time, few therapeutic approaches have been so far undertaken to correct the overall mitochondrial dysfunction in DS patients

Summary

Introduction

Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 (TS21) in which the specific phenotypic manifestations may result from the balance among genetic, environmental and stochastic events (Rachidi and Lopes 2007; Reeves et al 2001). In human primary lines of DS fetal fibroblasts, TS21 demonstrated to perturb the expression of genes involved in mitochondrial pathways, to decrease oxygen consumption and ATP content, to increase mtCa2+ load and ROS production (Piccoli et al 2013; Izzo et al 2017b).

Results

Conclusion