OBJECTIVE OPA1 mutations cause protein haploinsufficiency leading to dominant optic atrophy (DOA), an incurable retinopathy with variable severity. Up to 20% of patients also develop extraocular neurological complications. The mechanisms that cause this optic atrophy or its syndromic forms are still unknown. After identifying oxidative stress in a mouse model of the pathology, we sought to dete...

The citB gene of Bacillus subtilis encodes aconitase, the enzyme of the Krebs citric acid cycle, which is responsible for the interconversion of citrate and isocitrate. A B. subtilis strain with an insertion mutation in the citB gene was devoid of aconitase activity and aconitase protein, required glutamate for growth in minimal medium, and was unable to sporulate efficiently in nutrient broth ...

Friedreich's ataxia (FRDA), the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (T...

The aconitase of Sulfolobus solfataricus, a hyperthermophilic crenarchaeon, was cloned and heterologously expressed in Escherichia coli. Enzymic analyses and EPR measurements indicated clearly that the iron-sulphur cluster of the thermophilic aconitase was already inserted in the mesophilic host. The enzyme was purified to a specific activity of approx. 44 units/mg and to 90% homogeneity. The e...

specific concentration or orientation previously proposed. 4. The inhibitory effects were much reduced by the presence of phosphate or by preincubation with 5 mm-i8ocitrate. 5. In the presence of sodium chloride the activity of the aconitase increased. With potassium chloride there was an increase followedby a fall. An increase in the concentration of both salts much reduced the inhibition of f...

The fluorocitrate isomer that is a strong inhibitor and inactivator of aconitase has been shown by x-ray crystallographic studies on the rubidium ammonium salt to have the configurations (1R : 2R) or (1S : 2S) 1-fluoro-2-hydroxy-1,2,3-propanetricarboxylic acid. A possible mechanism for the action of fluorocitrate is proposed which involves the 1R : 2R isomer suggested from biochemical data.

Expression of two genes of unknown function, Staphylococcus aureus scdA and Neisseria gonorrhoeae dnrN, is induced by exposure to oxidative or nitrosative stress. We show that DnrN and ScdA are di-iron proteins that protect their hosts from damage caused by exposure to nitric oxide and to hydrogen peroxide. Loss of FNR-dependent activation of aniA expression and NsrR-dependent repression of nor...

We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms. ...

Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs) that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs) of the 5'- or 3'-untranslated regions (UTR) of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from t...

Aconitase is a mitochondrial enzyme that converts citrate to isocitrate in the tricarboxylic acid cycle and is inactivated by reactive oxygen species (ROS). We investigated the effect of exercise/contraction, which is associated with elevated ROS production, on aconitase activity in skeletal muscle. Humans cycled at 75% of maximal workload, followed by six 60-s bouts at 125% of maximum workload...