Mitochondrial Genes
Located within mitochondria and a key regulator of mitochondrial growth and respiratory function, PGC-1a, is known as a transcriptional co-activator (meaning it activates other genes), and is down-regulated in DS. PGC-1a has a downstream effect on other transcriptional partners such as ERRa, NRF1 and NRF2 which regulate mitochondrial genes (NEMGs). All of these were found to be down regulated in DS fetal heart tissue.
T21 Genes and Mitochondrial Dysfunction
Within the ‘Down Syndrome Critical Region’ (DSCR) located on Chromosome 21, sits a number of over-expressed genes involved in the development of DS characteristics due to the up or down regulation of their gene targets. They include DYRK1A, which balances brain development, RCAN1 controls immune response and cell growth, CBS an enzyme in the homocysteine/ transulfuration pathway and SOD1 involved in regulation of oxidative stress, miR-155 a multifunctional microRNA with widepread involvement in biological and pathological processes.
A gene which maps to Chromosome 21 (Hsa21) known as NRIP1 is responsible for supressing PGC-1a. NRIP1 is consistently overexpressed in DS cells and tissues and studies show that reducing NRIP1 overexpression increases PGC-1a and NEMGs and restores mitochondrial function. In addition, two other genes located on Hsa21, DYRK1A and RCAN1 are also thought to affect mitochondrial activity. Even slight increases in DYRK1A expression decreases NFATc activity and levels. Reduced NFATc decreases enzyme activity of electron transport chain (ATP production) and mitochondrial activity in heart musle cells.
Up regulation of RCAN1, also known as calcipressin, promotes mitochondrial dysfunction through reduced calcium stability. It changes mitochondrial dynamics and alters their expression by inhibiting NFAT. Changes in mitochondrial number, size and membrane potential as well as increased mitochondrial oxidative stress production occur due to oxidative stress produced by over expressed RCAN1.
SOD1 is another source of increased oxidative stress, and is located on Hsa21. Elevated levels of SOD1 compared to catalase and glutathione result in accumulation of hydrogen peroxide (H202). Studies on mice over expressing SOD1 reported learning and memory deficits, swelling of mitochondria, low ATP production and irreversible cell injury.
Overproduction of APP, a gene located on Hsa21, is associated with decreased COX (inflammation signalling) activity as well as mitochondrial abnormalities, although DS mice without the APP gene also showed reduced mitochondrial function and ATP production. MiR-155, mapped to Hsa21, regulates mitochondrial growth via targeting TFAM (mitochondrial transcription factor A).
Cultured DS astrocytes (insulation for neurons) and neurons (nerve cells) were found to have altered shapes with increased mitochondrial fragmentation. It is thought that the balance between mitochondrial fusion and fission (splitting and enlarging of the cells during biogenesis (growth)) determies mitochondrial structure and shape. Changes in the mitochondrial shape regulate crucial cellular functions.
Two genes involved in cellular fusion (splitting), MFN2 and OPA1 are downregulated in DS cells. Fetal cells under microscope showed a significant number of damaged mitochondria broken, shorter and swollen. OPA1 is responsible for maintaining and remodelling mitochondrial shape in addition to its role in mitochondrial fusion.
Down regulation of genes associated with ATP production combined with changes in cellular activity and shape, create widespread deficiency in energy production which causes excessive oxidative stress (ROS) in DS mitochondria.
The overproduction of ROS, as a result of poor mitochondrial function, is thought to play a role in the development of DS pathology. Increased oxidative stress levels are documented in embryonic life as well as human T21 fetal cells. Although changes in mitochondrial function and activity, and the overproduction of ROS are not considered the main cause of DS characteristics, they may play a role in the development of DS pathologies.
