Increased ROS generation and SOD activity in heteroplasmic tissues of transmitochondrial mice with A3243G mitochondrial DNA mutation

Li, Jian; Zhou, Kaixiang; Meng, Xia; Wu, Qin; S, Li; Y, Liu; Wang, J

doi:10.4238/vol7-4gmr480

Cited by 21 publications

(12 citation statements)

References 25 publications

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“…(Rustin et al, 2002). Besides, elevated levels of superoxides are also produced by the flavin radicals of complex I in patients with Complex I deficiency and in tissues of transmitochondrial mice with the m.3243A>G mutation (Raha and Robinson, 2000, Li et al, 2008). Studies using the m.3243A>G cybrids have demonstrated that RC defects caused by the high levels of mutation have resulted in increased oxidative stress (Wong and Cortopassi, 1997, Pang et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier

2009

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MELAS is a common mitochondrial disease frequently associated with the m.3243A>G point mutation in the tRNA Leu(UUR of mitochondrial DNA and characterized by strokelike episodes with vasogenic edema and lactic acidosis. The pathogenic mechanism of stroke and brain edema is not known. Alterations in the blood brain barrier, (BBB) caused by respiratory chain defects in the cortical microvessels could explain the pathogenesis. To test this hypothesis we developed a tissue culture model of the human BBB. The MELAS mutation was introduced into immortalized brain capillary endothelial cells and astrocytes. Respiratory chain activity and transendothelial electrical resistance, TEER was measured. Severe defects of respiratory chain complex I and IV activities, and a moderate deficiency of complex II activity in cells harboring the MELAS mutation were associated with low TEER, indicating that the integrity of the BBB was compromised. These data support our hypothesis that respiratory chain defects in the components of the BBB cause changes in permeability.

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Section: Discussionmentioning

confidence: 99%

The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier

2009

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“…ROS in the vasculature are produced by several enzymatic systems, including xanthine oxidase, nitric oxide synthases and nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidases. Previous studies have indicated that NAD(P)H oxidases are major factors involved in the aberrant production of ROS in the vasculature (7,8). Cumulative evidence has demonstrated that ROS are essential in the pathogenesis of various types of cardiovascular disease, including stroke and atherosclerotic lesions (9).…”

Section: Introductionmentioning

confidence: 99%

Association between the nicotinamide adenine dinucleotide phosphate oxidase p22phox gene -A930G polymorphism and intracerebral hemorrhage

Zhou¹,

Zhao

2015

Molecular Medicine Reports

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The present study aimed to evaluate whether the ‑A930G polymorphism of the nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase p22phox gene is involved in intracerebral hemorrhage (ICH) in the Chinese Han population. In the present case‑control investigation, the subjects included 118 patients with ICH and 147 healthy controls. The ‑A930G polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. Furthermore, the correlation between the ‑A930G gene polymorphism and ICH was evaluated using statistical analyses. The distribution of p22phox ‑A930G genotypes differed significantly between the two groups (P=0.003), with the AA, AG and GG genotype frequencies being 61.9, 29.3 and 8.8% in the control group and 40.7, 45.8 and 13.6% in the ICH group, respectively. The G allele frequency was significantly higher in patients with ICH compared with healthy controls (36.4 vs. 23.5%; P<0.05), however, the opposite was observed in the frequency of the A allele (63.6 vs. 76.5%; P<0.05). Binary logistic regression analysis revealed that genetic mutations of the p22phox ‑A930G gene were independent risk factors of ICH (odds ratio, 2.196; 95% confidence interval, 1.003‑4.586; P=0.009). In addition, certain conventional factors were associated with increased risk of ICH, including elevated blood pressure, increased levels of glucose and triglycerides in the blood, a history of hypertension and smoking. The ‑A930G polymorphism of the p22phox gene may affect the susceptibility to ICH and certain haplotypes of the gene may be associated with a higher susceptibility to ICH.

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“…The levels of ventricular C�F lactate correlate with the severity of neurological impairment [154] . Besides, the increase in brain RO� activity was demonstrated in MELA� [155] , as it was also clearly documented in HE [53] . MELA� experimental studies in cybrids showed that severe defects in protein synthesis and respiratory chain function segregate with the mutation, although the patho�� genic threshold is high; more than 90% mutant mtDNAs are required to cause dysfunction [153] .…”

Section: Sharing Pathways: Mitochondrial Encephalopathy Lactic Acidomentioning

confidence: 91%

“…The strokes, non��ischemic in origin and therefore called �stroke��like episodes��, are at least partially revers�� ible and do not conform to distribution of large cerebral arteries, but rather affect small arterioles and capillaries of the cortex while sparing the adjacent white matter [155] . The recurrent strokes are associated with vasogenic edema, as demonstrated by MR diffusion weighted imag�� ing studies, suggesting that they may be due to increased March 27, 2012|Volume 4|Issue 3| WJH|www.wjgnet.com 58 Perazzo JC et al .…”

Section: Sharing Pathways: Mitochondrial Encephalopathy Lactic Acidomentioning

confidence: 99%

Hepatic encephalopathy: An approach to its multiple pathophysiological features

Perazzo¹,

Tallis²,

Delfante³

et al. 2012

WJH

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Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two-to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly ex-HE is rapidly ex-HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics.

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Increased ROS generation and SOD activity in heteroplasmic tissues of transmitochondrial mice with A3243G mitochondrial DNA mutation

Cited by 21 publications

References 25 publications

The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier

The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier

Association between the nicotinamide adenine dinucleotide phosphate oxidase p22phox gene -A930G polymorphism and intracerebral hemorrhage

Hepatic encephalopathy: An approach to its multiple pathophysiological features

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