Oxidative Stress is Involved in Friedreich’s Ataxia Pathogenesis

Patrícia Silva, PhD avatar

by Patrícia Silva, PhD |

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Endoplasmic reticulum stress

Researchers at the University of California, Davis (UC Davis) recently conducted a review study on data concerning the link between oxidative stress and inherited mitochondrial diseases like Friedreich’s ataxia. The study was published in the journal Free Radical Biology and Medicine and is entitled “Oxidative stress in inherited mitochondrial diseases”.

Mitochondrial diseases are rare disorders caused by DNA mutations in mitochondrially-expressed genes. The five most common mitochondrial diseases are: Friedreich’s ataxia, Leber’s hereditary optic neuropathy (LHON), Leigh syndrome (LS), mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF). Currently, there is no approved or effective therapy for any of these conditions.

Mitochondria are small organelles considered the powerhouses of the cells where the energy for the body is produced. Mitochondria are a source of reactive oxygen species (ROS), which, when present in high levels, can induce significant damage to cell structures. This imbalance between ROS production and antioxidant systems is referred to as oxidative stress. In this study, UC Davis researchers reviewed the involvement of oxidative stress in the pathogenesis of the most common mitochondrial diseases.

Friedreich’s ataxia, in particular, is a rare inherited neurodegenerative disease characterized by progressive damage of the nervous system with degeneration of the spinal cord and peripheral nerves that leads to muscle weakness, sensory loss, balance deficits and lack of voluntary coordination of muscle movements. The disease is caused by a mutation in a mitochondrially-expressed gene called frataxin (FXN) that leads to a defective expression of the frataxin protein. Disease onset is usually during childhood or adolescence and the disorder leads to progressive disability, dependence on a wheelchair and reduced life expectancy.

Studies using Friedreich’s ataxia patient cells and animal models have shown that the antioxidant responses for protection against ROS are deficient in the context of the disease. In addition, patients exhibit an increase in ROS levels and oxidative damage. Oxidative stress by itself can promote inflammation, which in turn can cause oxidative stress, generating a vicious cycle that ultimately causes cell death.

According to the authors, the current model of Friedreich’s ataxia is that the decrease in frataxin protein levels leads to a reduction of the antioxidant protection triggering neuro-inflammatory and neurodegenerative effects that result in the clinical symptoms of the disease.

In terms of therapeutic options, there is no specific treatment that can halt disease progression in Friedreich’s ataxia patients, although a number of drugs are currently being tested. Given the evidence for the involvement of oxidative stress in disease pathogenesis, therapeutic strategies based on antioxidants (like idebenone, an analog of coenzyme Q10 antioxidant) are being evaluated. Therapeutic strategies aiming at increasing frataxin expression are also being tested.

In the review, the authors concluded that there is evidence supporting the involvement of oxidative stress in all five mitochondrial diseases analyzed, but that this link is especially observed in Friedreich’s ataxia. The team suggests that given the fact that oxidative stress underlies the pathogenesis of mitochondrial diseases, antioxidant therapies should be considered as a potential treatment strategy, particularly for Friedreich’s ataxia patients.