Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.3.5.1 (
succinate dehydrogenase
)
8,177
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Rett syndrome
(
RTT
) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in
MeCP2
-deficient mouse models suggest the involvement of oxidative stress in
RTT
pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of
MeCP2
-308 heterozygous female mice, a condition that more closely recapitulates that of
RTT
patients. The marked increase in the rate of hydrogen peroxide generation in the brain of
RTT
mice seems mainly produced by the dysfunctional
complex II
of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in
RTT
mouse brains when succinate, the
complex II
respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of
RTT
mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an
RTT
mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In
RTT
brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in
RTT
mouse brain and highlight CNF1 efficacy in counteracting
RTT
-related mitochondrial defects.
...
PMID:Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1. 2570 79
Rett syndrome
(
RTT
), an X chromosome-linked neurodevelopmental disorder affecting almost exclusively females, is associated with various mitochondrial alterations. Mitochondria are swollen, show altered respiratory rates, and their inner membrane is leaking protons. To advance the understanding of these disturbances and clarify their link to redox impairment and oxidative stress, we assessed mitochondrial respiration in defined brain regions and cardiac tissue of male wildtype (WT) and
MeCP2
-deficient (
Mecp2
-/y
) mice. Also, we quantified for the first time neuronal redox-balance with subcellular resolution in cytosol and mitochondrial matrix. Quantitative roGFP1 redox imaging revealed more oxidized conditions in the cytosol of
Mecp2
-/y
hippocampal neurons than in WT neurons. Furthermore, cytosol and mitochondria of
Mecp2
-/y
neurons showed exaggerated redox-responses to hypoxia and cell-endogenous reactive oxygen species (ROS) formation. Biochemical analyzes exclude disease-related increases in mitochondrial mass in
Mecp2
-/y
hippocampus and cortex. Protein levels of complex I core constituents were slightly lower in
Mecp2
-/y
hippocampus and cortex than in WT; those of complex V were lower in
Mecp2
-/y
cortex. Respiratory supercomplex-formation did not differ among genotypes. Yet, supplied with the
complex II
substrate succinate, mitochondria of
Mecp2
-/y
cortex and hippocampus consumed more O
2
than WT. Furthermore, mitochondria from
Mecp2
-/y
hippocampus and cortex mediated an enhanced oxidative burden. In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in
RTT
. Intensified mitochondrial O
2
consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in
RTT
.
...
PMID:Neuronal Redox-Imbalance in Rett Syndrome Affects Mitochondria as Well as Cytosol, and Is Accompanied by Intensified Mitochondrial O
2
Consumption and ROS Release. 3111 6
