Mt-Nd2a suppresses reactive oxygen species production by mitochondrial complexes I and III

被引:44
作者
Gusdon, Aaron M. [1 ,2 ]
Votyakova, Tatyana V. [2 ]
Mathews, Clayton E. [1 ,2 ]
机构
[1] Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA
[2] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15213 USA
关键词
D O I
10.1074/jbc.M708801200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Reactive oxygen species (ROS) play a critical role in the pathogenesis of human diseases. A cytosine to adenine transversion in the mitochondrially encoded NADH dehydrogenase subunit 2 (mt-ND2, human; mt-Nd2, mouse) gene results in resistance against type 1 diabetes and several additional ROS-associated conditions. Our previous studies have demonstrated that the adenine-containing allele (mt-Nd2(a)) is also strongly associated with resistance against type 1 diabetes in mice. In this report we have confirmed that the cytosine-containing allele (mt-Nd2(c)) results in elevated mitochondrial ROS production. Using inhibitors of the electron transport chain, we show that when in combination with nuclear genes from the alloxan-resistant (ALR) strain, mt-Nd2c increases ROS from complex III. Furthermore, by using alamethicin-permeabilized mitochondria, we measured a significant increase in electron transport chain-dependent ROS production from all mt-Nd2(c)-encoding strains including ALR. mt(NOD), non-obese diabetic (NOD), and C57BL/6 (B6). Studies employing alamethicin and inhibitors were able to again localize the heightened ROS production in ALR. mtNOD to complex III and identified complex I as the site of elevated ROS production from NOD and B6 mitochondria. Using submitochondrial particles, we confirmed that in the context of the NOD or B6 nuclear genomes, mt-Nd2(c) elevates complex I-specific ROS production. In all assays mitochondria from mt-Nd2(a)-encoding strains exhibited low ROS production. Our data suggest that lowering overall mitochondrial ROS production is a key mechanism of disease protection provided by mt-Nd2(a).
引用
收藏
页码:10690 / 10697
页数:8
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共 62 条
[51]   Association of a 5178C→A (Leu237Met) polymorphism in the mitochondrial DNA with a low prevalence of myocardial infarction in Japanese individuals [J].
Takagi, K ;
Yamada, Y ;
Gong, JS ;
Sone, T ;
Yokota, M ;
Tanaka, M .
ATHEROSCLEROSIS, 2004, 175 (02) :281-286
[52]   Mitochondrial genotype associated with longevity and its inhibitory effect on mutagenesis [J].
Tanaka, M ;
Gong, JS ;
Zhang, J ;
Yamada, Y ;
Borgeld, HJ ;
Yagi, K .
MECHANISMS OF AGEING AND DEVELOPMENT, 2000, 116 (2-3) :65-76
[53]   Life extension through neurofibromin mitochondrial regulation and antioxidant therapy for neurofibromatosis-1 in Drosophila melanogaster [J].
Tong, James Jiayuan ;
Schriner, Samuel E. ;
McCleary, David ;
Day, Brian J. ;
Wallace, Douglas C. .
NATURE GENETICS, 2007, 39 (04) :476-485
[54]   Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson's disease [J].
Tretter, L ;
Sipos, I ;
Adam-Vizi, V .
NEUROCHEMICAL RESEARCH, 2004, 29 (03) :569-577
[55]   A mitochondrial genotype associated with the development of autoimmune-related type 1 diabetes [J].
Uchigata, Y ;
Okada, T ;
Gong, JS ;
Yamada, Y ;
Iwamoto, Y ;
Tanaka, M .
DIABETES CARE, 2002, 25 (11) :2106-2106
[56]   Myocardial ischemia-reperfusion injury, antioxidant enzyme systems, and selenium: A review [J].
Venardos, Kylle M. ;
Kaye, David M. .
CURRENT MEDICINAL CHEMISTRY, 2007, 14 (14) :1539-1549
[57]   Detection of hydrogen peroxide with Amplex Red: interference by NADH and reduced glutathione auto-oxidation [J].
Votyakova, TV ;
Reynolds, IJ .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2004, 431 (01) :138-144
[58]   Ca2+-induced permeabilization promotes free radical release from rat brain mitochondria with partially inhibited complex I [J].
Votyakova, TV ;
Reynolds, IJ .
JOURNAL OF NEUROCHEMISTRY, 2005, 93 (03) :526-537
[59]   Δψm-dependent and -independent production of reactive oxygen species by rat brain mitochondria [J].
Votyakova, TV ;
Reynolds, IJ .
JOURNAL OF NEUROCHEMISTRY, 2001, 79 (02) :266-277
[60]   Crystal structure of the cytochrome bc(1) complex from bovine heart mitochondria [J].
Xia, D ;
Yu, CA ;
Kim, H ;
Xian, JZ ;
Kachurin, AM ;
Zhang, L ;
Yu, L ;
Deisenhofer, J .
SCIENCE, 1997, 277 (5322) :60-66