Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial labile iron (LI) is a major contributor to the susceptibility of skin fibroblasts to ultraviolet A (UVA)-induced oxidative damage leading to necrotic cell death via ATP depletion. Mitochondria iron overload is a key feature of the neurodegenerative disease Friedreich's ataxia (FRDA). Here we show that cultured primary skin fibroblasts from FRDA patients are 4 to 10-fold more sensitive to UVA-induced death than their healthy counterparts. We demonstrate that FRDA cells display higher levels of mitochondrial LI (up to 6-fold on average compared to healthy counterparts) and show higher increase in mitochondrial reactive oxygen species (ROS) generation after UVA irradiation (up to 2-fold on average), consistent with their differential sensitivity to UVA. Pre-treatment of the FRDA cells with a bespoke mitochondrial iron chelator fully abrogates the UVA-mediated cell death and reduces UVA-induced damage to mitochondrial membrane and the resulting ATP depletion by a factor of 2. Our results reveal a link between FRDA as a disease of mitochondrial iron overload and sensitivity to UVA of skin fibroblasts. Our findings suggest that the high levels of mitochondrial LI in FRDA cells which contribute to high levels of mitochondrial ROS production after UVA irradiation are likely to play a crucial role in the marked sensitivity of these cells to UVA-induced oxidative damage. This study may have implications not only for FRDA but also for other diseases of mitochondrial iron overload, with the view to develop topical mitochondria-targeted iron chelators as skin photoprotective agents.
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PMID:The role of mitochondrial labile iron in Friedreich's ataxia skin fibroblasts sensitivity to ultraviolet A. 3077 28

The mitochondrion is an essential organelle important for the generation of ATP for cellular function. This is especially critical for cells with high energy demands, such as neurons for signal transmission and cardiomyocytes for the continuous mechanical work of the heart. However, deleterious reactive oxygen species are generated as a result of mitochondrial electron transport, requiring a rigorous activation of antioxidative defense in order to maintain homeostatic mitochondrial function. Indeed, recent studies have demonstrated that the dysregulation of antioxidant response leads to mitochondrial dysfunction in human degenerative diseases affecting the nervous system and the heart. In this review, we outline and discuss the mitochondrial and oxidative stress factors causing degenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and Friedreich's ataxia. In particular, the pathological involvement of mitochondrial dysfunction in relation to oxidative stress, energy metabolism, mitochondrial dynamics, and cell death will be explored. Understanding the pathology and the development of these diseases has highlighted novel regulators in the homeostatic maintenance of mitochondria. Importantly, this offers potential therapeutic targets in the development of future treatments for these degenerative diseases.
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PMID:The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis. 3105 91

Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.
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PMID:Friedreich ataxia- pathogenesis and implications for therapies. 3149 82

Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi warrants investigation. We first establish that the human, honeybee, earthworm and fungal SDHs are all sensitive to the eight SDHIs tested, albeit with varying IC50 values, generally in the micromolar range. In addition to SDH, we observed that five of the SDHIs, mostly from the latest generation, inhibit the activity of RC complex III. Finally, we show that the provision of glucose ad libitum in the cell culture medium, while simultaneously providing sufficient ATP and reducing power for antioxidant enzymes through glycolysis, allows the growth of RC-deficient cells, fully masking the deleterious effect of SDHIs. As a result, when glutamine is the major carbon source, the presence of SDHIs leads to time-dependent cell death. This process is significantly accelerated in fibroblasts derived from patients with neurological or neurodegenerative diseases due to RC impairment (encephalopathy originating from a partial SDH defect) and/or hypersensitivity to oxidative insults (Friedreich ataxia, familial Alzheimer's disease).
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PMID:Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells. 3169 8

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease with developmental features caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently, ATP production abnormalities. Based on the involvement of such processes in FRDA, initial pathophysiological hypotheses focused on reactive oxygen species (ROS) production as a key component of the mechanism. With further study, a variety of other events appear to be involved, including abnormalities of mitochondrially related metabolism and dysfunction in mitochondrial biogenesis. Consequently, present therapies focus not only on free radical damage, but also on control of metabolic abnormalities and correction of mitochondrial biogenesis. Understanding the multitude of abnormalities in FRDA thus offers possibilities for treatment of this disorder.
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PMID:Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease. 3271 92

Calcium is utilised by cells in signalling and in regulating ATP production; it also contributes to cell survival and, when concentrations are unbalanced, triggers pathways for cell death. Mitochondria contribute to calcium buffering, meaning that mitochondrial calcium uptake and release is intimately related to cytosolic calcium concentrations. This review focuses on the proteins contributing to mitochondrial calcium homoeostasis, the roles of the mitochondrial permeability transition pore (MPTP) and mitochondrial calcium-activated proteins, and their relevance in neurodegenerative pathologies. It also covers alterations to calcium homoeostasis in Friedreich ataxia (FA).
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PMID:Mitochondrial calcium signalling and neurodegenerative diseases. 3271 93

In addition to ATP synthesis, mitochondria are highly dynamic organelles that modulate apoptosis, ferroptosis, and inflammasome activation. Through executing these varied functions, the mitochondria play critical roles in the development and progression of neurodegenerative diseases including Alzheimer disease, Parkinson disease, Huntington disease, and Friedreich ataxia, among others. Impaired mitochondrial biogenesis and abnormal mitochondrial dynamics contribute to mitochondrial dysfunction in these diseases. Additionally, dysfunctional mitochondria play critical roles in signaling for both inflammasome activation and ferroptosis. Therapeutics are being developed to circumvent inflammasome activation and ferroptosis in dysfunctional mitochondria. Targeting these aspects of mitochondrial dysfunction may present viable therapeutic strategies for combatting the neurodegenerative diseases. This review aims to summarize the role of the mitochondria in the development and progression of neurodegenerative diseases and to present current therapeutic approaches that target mitochondrial dysfunction in these diseases.
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PMID:Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. 3325 96


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