Biochemistry of Oxidative Stress

The Biochemistry of Oxidative Stress group analyzes the alteration of mitochondrial functions in Friedreich Ataxia (FA), a rare, cardio-neurodegenerative disease caused by deficient levels of frataxin, a mitochondrial protein. This deficit is due to mutations (mostly GAA triplet insertions) in the FXN gene. The most important features are, among others, ataxia, dysarthria, cardiac hypertrophy; some patients also develop diabetes.

To study this pathology, the group uses primary cultures of neurons -obtained from the dorsal root ganglion- and cardiomyocytes, which are the tissues most affected in this disease, and fibroblast cell lines derived from patients. We have also incorporated a new mouse model FXNI151F, with a point mutation that involves a 95% reduction in normal frataxin levels and that shows functional features very close to those observed in FA patients.

At the molecular level, we have observed alterations in the mitochondrial proteome, in mitochondrial iron and calcium homeostasis that impact the redox state of proteins and levels of calcium transporters such as NCLX, mitochondrial pore opening, the function of complexes I-III of the electron transport chain that would affect the rate of respiration and ATP synthesis and, in summary, loss of mitochondrial functions. Based on the results obtained, and since there is currently no effective cure, we design therapeutic strategies trying to improve the patients' quality of life; in this sense, we are analyzing the effects of different compounds that increase frataxin levels such as calcitriol. We have observed that this vitamin restores altered levels of the aforementioned markers and, therefore, a pilot clinical trial is being carried out in collaboration with IDIBGI. We also test molecules such as leriglitazone, in collaboration with the company Minoryx Therapeutics, focused on restoring the mitochondrial membrane potential and/or mitochondrial biogenesis.