Exploring mitochondrial biomarkers for Friedreich's ataxia: a multifaceted approach (original) (raw)
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Translational Research, 2020
is an autosomal recessive genetic disease causing the defective gene product, frataxin. A body of literature has been focused on the attempts to counteract frataxin deficiency and the consequent iron imbalance, in order to mitigate the disease-associated pro-oxidant state and clinical course. The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane. A body of evidence points to the strong antioxidant properties of these cofactors, and to their potential contribution in mitoprotective strategies in Friedreich's Ataxia clinical evolution. Thus, we suggest the rationale for planning combination strategies based on the 3 mitochondrial cofactors and of some antioxidants and iron binders as mitoprotective cocktails in Friedreich Ataxia patients, calling attention to clinical practitioners of the importance to implement clinical trials.
Neuronal Signaling
Friedreich ataxia (FRDA) is a recessive disorder resulting from relative deficiency of the mitochondrial protein frataxin. Frataxin functions in the process of iron–sulfur (Fe–S) cluster synthesis. In this review, we update some of the processes downstream of frataxin deficiency that may mediate the pathophysiology. Based on cellular models, in vivo models and observations of patients, ferroptosis may play a major role in the pathogenesis of FRDA along with depletion of antioxidant reserves and abnormalities of mitochondrial biogenesis. Ongoing clinical trials with ferroptosis inhibitors and nuclear factor erythroid 2-related factor 2 (Nrf2) activators are now targeting each of the processes. In addition, better understanding of the mitochondrial events in FRDA may allow the development of improved imaging methodology for assessing the disorder. Though not technologically feasible at present, metabolic imaging approaches may provide a direct methodology to understand the mitochondri...
Mitochondrial pathophysiology in Friedreich's ataxia
Journal of Neurochemistry, 2013
Neurological examination indicates that Friedreich's ataxia corresponds to a mixed sensory and cerebellar ataxia, which affects the proprioceptive pathways. Neuropathology and pathophysiology of Friedreich's ataxia involves the peripheral sensory nerves, dorsal root ganglia, posterior columns, the spinocerebellar, and corticospinal tracts of the spinal cord, gracile and cuneate nuclei, dorsal nuclei of Clarke, and the dentate nucleus. Involvement of the myocardium and pancreatic islets of Langerhans indicates that it is also a systemic disease. The pathophysiology of the disease is the consequence of frataxin deficiency in the mitochondria and cells. Some of the biological consequences are currently recognized such as the effects on iron-sulfur cluster biogenesis or the oxidative status, but others deserve to be studied in depth. Among physiological aspects of mitochondria that have been associated with neurodegeneration and may be interesting to investigate in Friedreich's ataxia we can include mitochondrial dynamics and movement, communication with other organelles especially the endoplasmic reticulum, calcium homeostasis, apoptosis, and mitochondrial biogenesis and quality control. Changes in the mitochondrial physiology and transport in peripheral and central axons and mitochondrial metabolic functions such as bioenergetics and energy delivery in the synapses are also relevant functions to be considered. Thus, to understand the general pathophysiology of the disease and fundamental pathogenic mechanisms such as dying-back axonopathy, and determine molecular, cellular and tissue therapeutic targets, we need to discover the effect of frataxin depletion on mitochondrial properties and on specific cell susceptibility in the nervous system and other affected organs.
Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia
Cell Death & Disease, 2016
Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, c...
Annals of Neurology, 2001
Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy ( 31 P-MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31 P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q 10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% ( p ؍ 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% ( p ؍ 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease-modifying strategy in this neurodegenerative disorder.
Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia
Journal of the Neurological Sciences, 2005
There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species ...
Predictors of progression in patients with Friedreich ataxia
Movement Disorders, 2008
Friedreich ataxia is an inherited, progressive, neurodegenerative disorder that is clinically heterogeneous. It is caused by a trinucleotide (GAA) repeat expansion resulting in frataxin loss and oxidative stress. We assessed clinical features including the development of cardiomyopathy and scoliosis and disease progression including loss of ambulation and interference with activities of daily living relative to the length of the GAA repeat, age of onset, and age of diagnosis in a retrospective cohort study of 61 genetically confirmed patients. The use of antioxidants such as vitamins, dietary supplements, and idebenone was also examined. Linear regression and Cox proportional hazard models assessed predictors to disease milestones. The shorter GAA allele accounted for part of the variability in the age of diagnosis (46%) and less in the age of onset (27%). Multivariate analysis demonstrated that age at diagnosis, which may incorporate other genetic and environmental factors, is more important than GAA length in predicting cardiomyopathy, scoliosis, and disease progression.