Intellectual Disability, Neurodegeneration and Mitochondria
Development of the DS brain is associated with a decreased number of neurons and abnormal neuronal processing. A common feature of people with DS is intellectual disability and the development of Alzheimer’s disease (AD). Clinical signs of AD are present in 75% of people with DS starting from 40 years of age. Its well known that the Chromosome 21 genes DYRK1A and RCAN1 affect NFAT activity which plays a pivotal role in both development and degeneration of neurons. DYRK1A affects the adaptability of neuronal synapses and the formation of memory. Its overexpression causes loss of cells in the hipocampus and degeneration of brain fibres.
In addition mitochondria are thought to play a role in neurodegeneration. DS mitochondria show changes in the shape of neurons and astrocytes and increased fragmentation of networks. People with DS have higher levels of oxidative stress and cell death. Mitochondrial dynamics including fusion/ fission, biogenesis and degeneration are critical for neurons to function efficiently. Mitochondrial function is essential for the formation of networks in the brain, calcium stability (altered in autism) (https://pubmed.ncbi.nlm.nih.gov/30992134/) (https://www.nature.com/articles/mp200863/) the transport of organelles within the cell, and energy production.
Functional and structural damage to mitochondria are thought to play a role in early stage neurodegenerative process as they don’t produce sufficient ATP and are more prone to producing oxidative stress and early cell death.
Energy depletion and oxidative stress can also induce changes in APP processing suggesting a potential link between mitochondrial dysfunction, oxidative stress, and Alzheimer’s disease (AD) plaque formation.
Research links significant alterations in APP processing and plaque formation in DS astrocytes and neurons. When mitochondria are inhibited in typical human brain cells, similar alterations occur. Mitochondrial function is altered in DS astrocytes, shown by reduced mitochondrial redox activity and membrane potential (movement of ions through a membrane).
Poor energy production in DS cells leads to alterations in APP activity resulting in accumulation of intracellular plaque formation. These results suggest that reduced mitochondrial energy metabolism in the DS brain may contribute to the formation of plaque and development of AD.
Hypotonia and Mitochondria
People with DS have low muscle tone and altered motor co-ordination with mitochondria involved in their development.
Skeletal muscle is vulnerable to oxidative stress due, partly to the rapid changes in energy supply and oxygen flux that occurs during contraction, resulting in increased electron flux and leakage from the mitochondrial electron transport chain. It has been recently shown that over-expression of PGC1α (opposite of DS) inhibits muscle wasting during fasting and loss of nerve supply. In addition the over expression of miR-155 leads to the suppression of MEF2A expression preventing mucle cell activity. Reduced mitochondrial activity and function activates muscular wasting in animals.
Analysis of DS muscle fibres showed changes in the mitochondria, also found in DS mice who exhibit motor dysfunction. Numerous pathways are altered in DS muscle, including ATP production, glucose and fat metabolism and transmission from neurons to muscles. People with DS have features of premature aging including a reduction in muscle strength similar to typical people of an older age. Therefore, its possible the low tone and motor dysfunction in Ds share similarities with age related decline in skeletal muscle mass, strength and quality.
Heart defects and mitochondria
Congenital heart defects are common in DS, the most frequent being AVSD’s followed by VSD’s and tetralogy of Fallot.
Analysis of human fetal heart tissues from DS subjects show down regulation of NEMGs (mitochondrial genes), especially enzymes involved in the
electron transport chain (ATP production).
DYRK1A and RCAN1, which play a role in the calcineurin/NFAT (enzymes in the electron transport chain) pathway are believed to affect mitochondrial activity and shape during heart development. Even moderate over expression of DYRK1A decreases NFATc activity and can cause vascular and cardiac defects during heart development.
In human DS fetal hearts, NFATc3 and NFATc4 were found significantly down regulated while DYRK1A and RCAN1, involved in regulating the levels of NFATc phosphorylation, were over-expressed due to dosage effect.
When mitochondria were analyzed, fibroblasts (connective tissue cell) from DS fetuses with congenital heart defects showed a chronic pro-oxidative state more pronounced with respect to fetuses without cardiopathy.
Significant differences in mitochondrial respiration, complex I activity (ATP production) and ROS production were observed, suggesting a relationship between mitochondrial function and cardiac phenotype.
NRIP1-dependent repression of genes involved in mitochondrial function may be linked also to the ventricular hypertrophy, which occurs in DS after birth, possibly as a result of reduced mitochondrial electron-transport chain activity and oxygen consumption. NRIP1 over expression
in a transgenic mouse results in cardiac hypertrophy. Alterations in mitochondrial function observed in right ventricular cardiac hypertrophy are mainly attributed to complex I (ATP porduction) dysfunction.
Also miR-155, triplicated in DS, a known supressor of the TFAM gene, may be responsible for heart hypertrophy. The authors suggest that inhibition of miR-155 could potentially correct this.
Complications of CHD in patients with DS are the development of pulmonary hypertension (PH) and other associated issues such as patent ductus arteriosus (PDA) and pulmonary stenosis. Both functional and structural alterations of mitochondria occur in PH. It has been reported that smooth muscle cells isolated from the pulmonary vessels of rats with PH show deficiencies in the activities of complexes I-III (ATP production), an increase in mitochondrial ROS generation and altered mitochondrial membrane potential (movement of ions across a membrane). In muscle cells from patients with PH, a disruption of normal mitochondrial components was noted.
Type 2 Diabetes and Obesity and Mitochondria
Children with DS have an increased risk of developing endocrine disorders like type 2 diabetes and childood obesity.
Type 2 diabetes and obesity develop due to poor mitochondrial dysfunction and energy production. Given the important role that mitochondria have for energy production, fat burning, and transport of nutrients, an impairment of electron transport chain (ATP production) activity may have particular relevance to the development of insulin resistance in type 2 diabetes.
A large reduction of electron transport chain (ATP production) activity was observed in the mitochondria of type 2 diabetic and obese subjects compared with unaffected volunteers. Mitochondria from skeletal muscle were small with reduced activity of complex I (ATP production) in both type 2 diabetes and obesity
NRIP1 and PGC-1α both play key roles in the regulation of genes involved in energy balance. The expression and promoter activity of CIDEA, (regulator of fat cell function and obesity), is supressed by NRIP1 and increased by PGC-1α, through ERRα and NRF-1 activity. NRIP1 and PGC-1α are involved in glucose uptake and the development of diabetes through regulation of the insulin sensitive glucose transporter GLUT4 expression.
Depletion of NRIP1 improves the metabolism in both muscles and glucose activity suggesting that NRIP1 may be a therapeutic target in the treatment of insulin resistance in obese and type 2 diabetic patients. In addition, mice lacking NRIP1 are lean, resistant to high-fat diet-induced obesity and have increased oxygen consumption.
Immune Disorders and Mitochondria
Children with DS have increased susceptibility to infections, usually of the upper respiratory tract and autoimmune disorders, including hypothyroidism and celiac disease. The abnormalities of the immune system associated with DS include: alteration of B and T-cell number, with marked decrease of lymphocytes, abnormal thymus function and development, impaired T cell production, reduced antibody responses to immunizations and defects of neutrophil activity. The rates of lymphocyte respiration in the children with DS were found slower than in the control group. These differences could reflect a relatively lower rate of mitochondrial energy conversion in DS children such as defects in the inner mitochondrial membrane.
A number of studies provide evidence that mitochondrial dysfunction plays a role in the major clinical symptoms of DS such as neuronal defects and low tone. In addition, mitochondrial inefficiency may contribute to an increase in conditions in which energy metabolism is involved such as heart defects, low muscle tone, Alzheimer’s disease, type 2 diabetes, obesity and immune disorders. Addressing mitochondrial imbalances will improve and prevent DS characteristics improving quality of life for people with DS and their families.
