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)

Frataxin deficiency is the main cause of Friedreich ataxia, an autosomal recessive neurodegenerative disorder. Frataxin function in mitochondria has not been fully explained yet. In this work, we show that Saccharomyces cerevisiae frataxin orthologue Yfh1p interacts physically with succinate dehydrogenase complex subunits Sdh1p and Sdh2p of the yeast mitochondrial electron transport chain and also with electron transfer flavoprotein complex ETFalpha and ETFbeta subunits from the electron transfer flavoprotein complex. Genetic synthetic interaction experiments confirmed a functional relationship between YFH1 and succinate dehydrogenase genes SDH1 and SDH2. We also demonstrate a physical interaction between human frataxin and human succinate dehydrogenase complex subunits, suggesting also a key role of frataxin in the mitochondrial electron transport chain in humans. Consequently, we suggest a direct participation of the respiratory chain in the pathogenesis of the Friedreich ataxia, which we propose to be considered as an OXPHOS disease.
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PMID:Frataxin interacts functionally with mitochondrial electron transport chain proteins. 1596 14

We are developing rapid immunoassays to measure the protein levels, enzymatic activities and post-translational modifications of mitochondrial proteins. These assays can be arrayed in multi-analyte panels for biomarker discovery and they can also be used individually at point of care where the level or activity of a small number proteins or even a single protein is highly informative. For example, we have characterized OXPHOS deficits associated with lipoatrophy, an adverse metabolic side-effect of anti-retroviral therapy, and have shown that OXPHOS deficits observed in vitro are also exhibited not only in clinically affected tissue (peripheral fat) but also in more easily accessible tissue (peripheral blood mononucleated cells). Similarly, we have shown that a small set of assays can be used to identify almost all patients with genetic deficits in OXPHOS complexes I or IV, the most common cause of inherited mitochondrial disease. Finally, we recently reported that Friedreich's Ataxia (FA) patients and carriers can be identified on the basis of a simple dipstick test to measure levels of a single protein, frataxin, an iron regulatory protein whose disrupted expression is the proximal cause of neurodegeneration in FA. Because each of these tests can be performed in an extremely simple, rapid dipstick format using non-invasive samples such as cheek swabs and fingerprick blood, they have potential for use as point of care diagnostics for mitochondrial disease and as front-line screening tools to help guide drug therapies and minimize adverse off-target drug effects.
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PMID:Novel antibody-based strategies for the rapid diagnosis of mitochondrial disease and dysfunction. 1946 Apr 56

Friedreich ataxia (FRDA) is a hereditary disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Patients with FRDA experience neurologic alterations and cardiomyopathy, which is the leading cause of death. The specific effects of frataxin depletion on cardiomyocytes are poorly understood because no appropriate cardiac cellular model is available to researchers. To address this research need, we present a model based on primary cultures of neonatal rat ventricular myocytes (NRVMs) and short-hairpin RNA interference. Using this approach, frataxin was reduced down to 5 to 30% of control protein levels after 7 days of transduction. At this stage the activity and amount of the iron-sulfur protein aconitase, in vitro activities of several OXPHOS components, levels of iron-regulated mRNAs, and the ATP/ADP ratio were comparable to controls. However, NRVMs exhibited markers of oxidative stress and a disorganized mitochondrial network with enlarged mitochondria. Lipids, the main energy source of heart cells, also underwent a clear metabolic change, indicated by the increased presence of lipid droplets and induction of medium-chain acyl-CoA dehydrogenase. These results indicate that mitochondria and lipid metabolism are primary targets of frataxin deficiency in NRVMs. Therefore, they contribute to the understanding of cardiac-specific mechanisms occurring in FRDA and give clues for the design of cardiac-specific treatment strategies for FRDA.
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PMID:Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism. 2475 25