Therapeutics for mitochondrial dysfunction-linked diseases in Down syndrome

Abstract

Genome-wide deregulation contributes to mitochondrial dysfunction and impairment in oxidative phosphorylation (OXPHOS) mechanism resulting in oxidative stress, increased production of reactive oxygen species (ROS) and cell death in individuals with Down syndrome (DS). The cells, which require more energy, such as muscles, brain and heart are greatly affected. Impairment in mitochondrial network has a direct link with patho-mechanism at cellular and systemic levels at the backdrop of generalized metabolic perturbations in individuals with DS. Myriads of clinico-phenotypic features, including intellectual disability, early aging and neurodegeneration, and Alzheimer disease (AD)-related dementia are inevitable in DS-population where mitochondrial dysfunctions play the central role. Collectively, the mitochondrial abnormalities and altered energy metabolism perturbs several signaling pathways, particularly related to neurogenesis, which are directly associated with cognitive development and early onset of AD in individuals with DS. Therefore, therapeutic challenges for amelioration of the mitochondrial defects were perceived to improve the quality of life of the DS population. A number of pharmacologically active natural compounds such as polyphenols, antioxidants and flavonoids have shown convincing outcome for reversal of the dysfunctional mitochondrial network and oxidative metabolism, and improvement in intellectual skill in mouse models of DS and humans with DS.

Keywords: Antioxidants; Diseases of Down syndrome; Down syndrome; Mitochondrial dysfunction; Mitochondrial therapeutics; Polyphenols.