Therapeutics for mitochondrial dysfunction-linked diseases in Down syndrome

Genome-wide deregulation contributes to mitochondrial dysfunction and impairment in oxidative phosphory-lation (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 in-dividuals 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 mito-chondrial dysfunctions play the central role. Collectively, the mitochondrial abnormalities and altered energy metabolism perturbs several signaling pathways, particularly related to neurogenesis, which are directly asso-ciated with cognitive development and early onset of AD in individuals with DS. Therefore, therapeutic chal-lenges 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.

Automated summary

Genome-wide deregulation leads to mitochondrial dysfunction in individuals with Down syndrome, resulting in oxidative stress, increased production of reactive oxygen species (ROS), and cell death. The impairment in mitochondrial network is closely linked to cellular and systemic pathology, causing various clinical manifestations such as intellectual disability, early aging, neurodegeneration, and Alzheimer's disease-related dementia. Therapeutic challenges involve improving mitochondrial defects using natural compounds like polyphenols, antioxidants, and flavonoids, which have shown promising outcomes in animal models and humans with Down syndrome.