Friedreich's ataxia (FRDA) is an autosomal recessive disorder that causes progressive damage to the nervous system. According to statistics, about one in 50,000 people in the world are affected by the ataxia of Friedreich. Friedreich is the most common recessive ataxia and is caused by insufficient expression of the mitochondrial protein frataxin
Mitochondria are cellular energy plants. Mitochondria rely on the electron transport of enzyme chains that contain iron-sulfur clusters to produce the energy. The energy is used for cellular metabolism. Frataxin plays a crucial role in ensuring the correct formation of iron-sulfur clusters in the enzyme. In cells with reduced levels of frataxin, abnormal iron-sulfur cluster formation leads to a decrease in energy production and iron accumulation, which induces cell destruction of reactive oxygen species (ROS). Damage caused by excessive ROS can lead to degeneration of spinal nerve tissue.
FRDA is a disease that is debilitating or even disabling. It affects movement and coordination related issues and may also cause other symptoms such as hearing and vision loss. There are currently no effective treatments for FRD.
A new study demonstrates that hypoxia restores levels of iron-sulfur clusters in cells and normalizes FRDA-related signaling events through cell and mouse models. This finding may help FRDA patients in the future, although its safety is yet to be determined.
Iron-sulfur clusters are redox proteins that are involved in important processes such as electron transport, gene expression, and regulation. The first spontaneous formation of iron-sulfur clusters was more than 2.5 billion years ago when the earth's atmosphere was almost oxygen-free. The evolutionary origins of these clusters have led Vamsi Mootha and his team to wonder whether oxygen in the environment could play a key role in FRDA.
The team cultured yeast, human cells, and nematodes rich in frataxin proteins at very low oxygen levels (1% ambient oxygen concentration). They found that these frataxin-rich cells and organisms thrive under hypoxic conditions.
Subsequently, the research team respectively gave two group of FRDA mice a hypoxic environment and a higher oxygen environment. Respiratory hypoxia slowed the progression of ataxia in mice, while higher oxygen promoted the progression of ataxia in mice. These results indicated that hypoxia restores levels of iron-sulfur clusters and normalizes FRDA-related signaling events.
Mootha believes that although these results suggest that breathing thin air may one day have therapeutic potential in the treatment of FRDA, no one should treat hypoxia as a temporary therapy. Because oxygen is essential for life, hypoxia is very dangerous. Human organs and tissue cells have a certain limit on the tolerance of hypoxia. Exceeding this so-called threshold will cause adverse reactions and even life-threatening. While these preliminary, basic results are promising, more research is needed to apply it in any clinical setting.