Triplication of HSA21 on alterations in structure and function of mitochondria.

Triplication of genes encoded in human chromosome 21 (HSA21) is responsible for the phenotypes of Down syndrome (DS). The dosage-imbalance of the nuclear genes and the extra-nuclear mitochondrial DNA (mtDNA) jointly contributes to patho-mechanisms in DS. The mitochondrial organelles are the power house of cells for generation of ATP and maintaining cellular calcium and redox homeostasis, and cellular energy-metabolism processes. Each cell contains hundreds to thousands of mitochondria depending on their energy consumption. The dynamic structure of mitochondria is maintained with continuous fission and fusion events, and thus, content of mtDNA and its genetic composition are widely variable among cells. Cells of brain and heart tissues of DS patients and DS-mouse models have demonstrated elevated number but reduced amount of mtDNA due to higher fission process. This mechanism perturbs the oxidative phosphorylation (OXPHOS) and generates more free radicals such as reactive oxygen species (ROS), suggesting contribution of mtDNA in proliferation and protection of cells from endogenous toxic environment and external stressors. Gene-dosage in DS population collectively contributes to mitochondrial dysfunction by lowering energy production and respiratory capacity via the impaired OXPHOS, and damaged redox homeostasis and mitochondrial dynamics in all types of cells in DS. The context is highly complex and affects the functioning of all organs. The effect in brain and heart tissues promotes myriads of neurodegenerative diseases and cardiac complexities in individuals with DS. Crosstalk between trisomic nuclear and mitochondrial genome has been crucial for identification of potential therapeutic targets.