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

Abstract

ABSTRACT. The mitochondrial A3243G tRNALeu(UUR) mutation associated with a variety of mitochondrial disorders results in a severe respiratory deficiency, an increase in reactive oxygen species (ROS) production and activities of anti-oxidative enzyme in vitro. However, the phenotypic implications of this mutation have not been described in vivo. Here, mitochondria carrying A3243G transition from the peripheral blood of diabetes mellitus patients were microinjected into zygotes. Influence of this mutation on mitochondrial respiratory enzyme activities, ROS generation, and antioxidative enzyme activities in the heteroplasmic tissues of transmitochondrial mice was evaluated. The chimeric mice exhibited a subtle impaired oxidative phosphorylation, reduced activity of complex I/IV, increased activity of superoxide dismutase, and in turn, enhanced ROS generation. Our results suggest that mitochondrial 1055 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 7 (4): 1054-1062 (2008) ROS generation and SOD activity in transmitochondrial mice A3243G mutation may be responsible for the high ROS production in vivo. Increased generation of ROS caused by mtDNA mutation may also play a role in the pathogenesis of the A3243G mutationassociated diseases.

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

“…(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).…”

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

“…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).…”

Hepatic encephalopathy: An approach to its multiple pathophysiological features

“…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] .…”

“…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 .…”