Dr Rosella Abeti and Prof Paola Giunti at the London Ataxia Centre, UCL Institute of Neurology, have shared results from their project which was funded by Ataxia UK. The project was titled ‘Exploring novel iron-mediated mechanisms to prevent cellular death in Friedreich’s Ataxia’.
Friedreich’s ataxia (FA) is a rare genetic condition that causes pr
ogressive damage to the nervous system and heart. People with FA have decreased levels of a protein called frataxin, which is needed for healthy mitochondria, the energy-producing parts of cells. When there is less frataxin, cells experience stress, leading to impaired function and death, particularly in nerve and heart tissue.
In this project, the researchers aimed to understand how a mitochondrial protein called mitoNEET is involved in the signalling of cellular stress in FA. MitoNEET can be targeted with existing drugs, making it a possible target for FA therapy. The researchers wanted to know whether mitoNEET helps cells cope with mitochondrial stress and whether boosting its function could restore balance in stressed cells.
To do this, they created a type of neuroblastoma cells in the lab, a human cell line often used to study neurodegenerative conditions. They then used the gene editing tool CRISPR to decrease frataxin protein levels in the cells, mimicking FA. They also created cells with increased mitoNEET levels. And finally, they created cells with mitoNEET removed.
They tested how the different types of cells responded to mitochondrial stress using a range of techniques, including measuring gene expression, and protein levels, both in normal conditions and with the addition of a form of iron, which is a stressor in FA.
The researchers saw that cells with lower frataxin showed abnormally high levels of stress-related markers, even without additional stress. When iron was added to these cells, the level of stress markers did not increase further, indicating that the stress signalling was already on overdrive and could not respond properly. When levels of mitoNEET were increased in the low-frataxin cells, the cells began behaving like healthy cells, with more balanced stress markers and a more normal response to iron overload.
With these results in mind, and with mitoNEET already having known drugs that can activate or inhibit it, this project suggests that existing medications could be repurposed to target mitoNEET in FA.
Read more about the project here.
