Differential requirements of calcium for oxoglutarate dehydrogenase and mitochondrial nitric-oxide synthase under hypoxia: Impact on the regulation of mitochondrial oxygen consumption

FXTAS (fragile X-associated tremor/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the permutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson’s disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.

show abstract

“…Cytosolic and intramitochondrial free Ca 2+ concentrations were evaluated as described previously using Fura-2 [17,18]. …”

Section: Methodsmentioning

confidence: 99%

Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Ross-Inta

Omanska-Klusek

Wong

et al. 2010

Biochemical Journal

Self Cite

169

203

View full text Add to dashboard Cite

show abstract

“…Thus mitochondria are still able to produce ATP at a significant rate, preventing a local point of anoxia. These effects were calculated at 220 M oxygen, concentrations considered hyperoxic for mitochondria; if hypoxic (or normoxic for mitochondria) conditions are considered (10 -20 M oxygen), these effects could be exacerbated (78). If cytosolic calcium concentrations increase further (e.g., 1 M [Ca 2ϩ ] cyt , equivalent to 2.3 M [Ca 2ϩ ] mt ) as mitochondria are located closer to microdomains with higher calcium concentration, 71% of the mitochondria motility may become arrested.…”

Section: Temporal Regulation Of No Productionmentioning

confidence: 99%

Nitric oxide regulation of mitochondrial oxygen consumption I: cellular physiology

Giulivi¹,

Kato²,

Cooper³

2006

American Journal of Physiology-Cell Physiology

Self Cite

109

View full text Add to dashboard Cite

Mitochondrial biochemistry is complex, expanding from oxygen consumption, oxidative phosphorylation, lipid catabolism, heme biosynthesis, to apoptosis, calcium homeostasis, and production of reactive oxygen species, including nitric oxide (NO). The latter molecule is produced by a mitochondrial NO synthase (mtNOS). The rates of consumption and production determine the steady-state concentration of NO at subcellular levels, leading to regulation of mitochondrial events. Temporospatial processes tightly regulate production of NO in mitochondria to maximize target effects and minimize deleterious reactions. Temporal regulatory mechanisms of mtNOS include activation by calcium signaling and transcriptional/translational regulations. Calcium-activated mtNOS inhibits mitochondrial respiration, resulting in a decrease of the oxygen consumption. This negative regulation antagonizes the effects of calcium on calcium-dependent dehydrogenases in the citric acid cycle, preventing the formation of anoxic foci. Temporal regulation of NO production by intracellular calcium signaling is a complex process, considering the heterogeneous intracellular calcium response and distribution. NO production in mitochondria is spatially regulated by mechanisms that determine subcellular localization of mtNOS, likely acylation and protein-protein interactions, in addition to transcriptional regulation as neuronal NOS. Because NO rapidly decays in mitochondria, subcellular localization of mtNOS is crucial for NO to function as a signal molecule. These temporospatial processes are biologically important to allow NO to act as an effective signal molecule to regulate mitochondrial events such as oxygen consumption and reactive oxygen species production.

show abstract

“…Percoll-purified coupled rat liver mitochondria (1 mg protein/sample) were incubated with 0.1 mM L-arginine or N G -monomethyl-L-arginine (NMMA) and a respiratory substrate in an incubation medium containing calcium in amounts shown to be sufficient to elicit sustained production of nitric oxide (65). At each time point (0, 30, 60, and 120 min), mitochondria were pelleted and washed extensively to remove remaining L-arginine or NMMA, and the mitochondrial proteins were analyzed using two-dimensional (2D) gels (25).…”

Section: Methodsmentioning

confidence: 99%

Nitration of specific tyrosines in F_oF₁ATP synthase and activity loss in aging

Haynes

Traaseth

Elfering

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

Haynes V, Traaseth NJ, Elfering S, Fujisawa Y, Giulivi C. Nitration of specific tyrosines in FoF1 ATP synthase and activity loss in aging. Am J Physiol Endocrinol Metab 298: E978 -E987, 2010. First published February 16, 2010 doi:10.1152/ajpendo.00739.2009.-It has been reported that C-nitration of proteins occurs under nitrative/oxidative stress; however, its role in pathophysiological situations is not fully understood. In this study, we determined that nitration of Tyr 345 and Tyr 368 in the ␤-subunit of the mitochondrial FoF1-ATPase is a major target for nitrative stress in rat liver under in vivo conditions. The chemical characteristics of these Tyr make them suitable for a facilitated nitration (solvent accessibility, consensus sequence, and pKa). Moreover, ␤-subunit nitration increased significantly with the age of the rats (from 4 to 80 weeks old) and correlated with decreased ATP hydrolysis and synthesis rates. Although its affinity for ATP binding was unchanged, maximal ATPase activity decreased between young and old rats by a factor of two. These changes directly impacted the available ATP concentration in vivo, and it was expected that they would affect multiple cellular ATP-dependent processes. For instance, at least 50% of available [ATP] in the liver of older rats would have to be committed to sustain maximal Na ϩ -K ϩ -ATPase activity, whereas only 30% would be required for young rats. If this requirement was not fulfilled, the osmoregulation and Na ϩ -nutrient cotransport in liver of older rats would be compromised. On the basis of our studies, we propose that targeted nitration of the ␤-subunit is an early marker for nitrative stress and aging. adenosine 5=-triphosphate; adenosine 5=-triphosphatase; mitochondria; bioenergetics; biomarker IT HAS BEEN SHOWN THAT MITOCHONDRIA produce nitric oxide and that this molecule modulates the oxygen consumption of the organelle by competitive and noncompetitive inhibition of cytochrome c oxidase (18,30). Inhibition of oxygen consumption is transient as long as small quantities of nitric oxide are generated. However, at high or sustained levels of nitric oxide, the inhibition of the respiratory chain leads to an increased rate of formation of oxygen-free radicals that may damage mitochondria and/or initiate apoptosis (30). Other studies have demonstrated novel roles for nitric oxide through S-nitrosation of proteins (Ref. 43 and references therein). The finding that protein modification by nitrosation may be dynamically regulated and, in certain cases, coupled to cell surface signals has potential implications for other signaling pathways and cellular control mechanisms.However, in addition to its transient effects mediated through interaction with cytochrome c oxidase and/or S-nitrosation of proteins, nitric oxide may exhibit relatively long-term effects through the nitration of proteins (32,38). It has been proposed that C-nitration of proteins constitutes a novel chemical modification that occurs as a consequence of the "normal" oxidative background (39...

show abstract

Differential requirements of calcium for oxoglutarate dehydrogenase and mitochondrial nitric-oxide synthase under hypoxia: Impact on the regulation of mitochondrial oxygen consumption

Cited by 21 publications

References 65 publications

Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Nitric oxide regulation of mitochondrial oxygen consumption I: cellular physiology

Nitration of specific tyrosines in F_oF₁ATP synthase and activity loss in aging

Contact Info

Product

Resources

About

Differential requirements of calcium for oxoglutarate dehydrogenase and mitochondrial nitric-oxide synthase under hypoxia: Impact on the regulation of mitochondrial oxygen consumption

Cited by 21 publications

References 65 publications

Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Nitric oxide regulation of mitochondrial oxygen consumption I: cellular physiology

Nitration of specific tyrosines in FoF1ATP synthase and activity loss in aging

Contact Info

Product

Resources

About

Nitration of specific tyrosines in F_oF₁ATP synthase and activity loss in aging