Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets

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.

Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation and Cellular Bioenergetics in Human Down Syndrome Fibroblasts

“…Down syndrome produces various developmental abnormalities during the fetal and neonatal life and leads to a host of pathophysiological events in adults, including various neurocognitive and metabolic impairments as well as neurodegeneration [1]. One of the biochemical hallmarks of Down syndrome is mitochondrial dysfunction which is believed to play a significant role in the pathogenesis of many of the functional defects associated with Down syndrome [2][3][4][5].…”

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

“…Mitochondrial dysfunction and increased oxidative stress have been previously found in the Ts1Cje brain (Shukkur et al, 2006). In fact, altered mitochondrial function has long been associated with DS (reviewed by Valenti et al, 2014;Izzo et al, 2018). It has been recently found damaged mitochondria linked to increased oxidative stress, reduced mitophagy and reduced autophagy, together with mTOR hyperactivation in fibroblasts from DS patients, (Bordi et al, 2019).…”

“…Accordingly, mitochondrial alterations have been described in DS and DS mouse models (reviewed by Valenti et al, 2014;Izzo et al, 2018). In fact, it has been recently shown that reduced autophagy/mitophagy due to mTOR hyperactivation produces damaged mitochondria accumulation in DS fibroblasts (Bordi et al, 2019).…”

Mitoprotective Clinical Strategies in Type 2 Diabetes and Fanconi Anemia Patients: Suggestions for Clinical Management of Mitochondrial Dysfunction

“…These links between FA and T2D are consistent with shared pathogenetic mechanisms, first including the role(s) of OS both in T2D and in FA. It is worth noting that excess T2D prevalence is not confined to FA, as far as a number of other genetic diseases [79][80][81][82][83] display excess T2D prevalence (along with OS features), independently of their multiple and different genetic deficiencies. Thus, the co-occurrence of T2D in these disorders suggests common deficiency(ies) focused on OS/MDF abnormalities.…”