Can a Single Subunit Yeast NADH Dehydrogenase (Ndi1) Remedy Diseases Caused by Respiratory Complex I Defects?

Yagi, Takao; Seo, Byoung Boo; Nakamaru‐Ogiso, Eiko; Marella, Mathieu; Barber-Singh, Jennifer; Yamashita, Tetsuo; Kao, Mou-Chieh; Matsuno‐Yagi, Akemi

doi:10.1089/rej.2006.9.191

Cited by 40 publications

(29 citation statements)

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“…Complex I (NADH-quinone oxidoreductase) is made up of 46 different subunits and is inhibited by rotenone (57). Increased mitochondrial O 2 Ϫ generation is indicated in diabetic vasculopathy and ischemia-reperfusion (46).…”

Section: Discussionmentioning

confidence: 99%

NADPH oxidase has a directional response to shear stress

Godbole¹,

Lu²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Godbole AS, Lu X, Guo X, Kassab GS. NADPH oxidase has a directional response to shear stress. Am J Physiol Heart Circ Physiol 296: H152-H158, 2009. First published November 14, 2008 doi:10.1152/ajpheart.01251.2007.-Vessel regions with predilection to atherosclerosis have negative wall shear stress due to flow reversal. The flow reversal causes the production of superoxides (O 2 Ϫ ), which scavenge nitric oxide (NO), leading to a decrease in NO bioavailability and endothelial dysfunction. Here, we implicate NADPH oxidase as the primary source of O 2 Ϫ during full flow reversal. Nitrite production and the degree of vasodilation were measured in 46 porcine common femoral arteries in an ex vivo system. Nitrite production and vasodilation were determined before and after the inhibition of NADPH oxidase, xanthine oxidase, or mitochondrial oxidase. NADPH oxidase inhibition with gp91ds-tat or apocynin restored nitrite production and vasodilation during reverse flow. Xanthine oxidase inhibition increased nitrite production at the highest flow rate, whereas mitochondrial oxidase inhibition had no effect. These findings suggest that the NADPH oxidase system can respond to directional changes of flow and is activated to generate O 2 Ϫ during reverse flow in a dose-dependent fashion. These findings have important clinical implications for oxidative balance and NO bioavailability in regions of flow reversal in a normal and compromised cardiovascular system. superoxide; nitric oxide; oxidative balance; reduced nicotinamide adenine dinucleotide phosphate NITRIC OXIDE (NO) is released by endothelial cells to regulate blood vessel diameter acutely as well as to maintain long-term homeostatic conditions of the vessel wall (4,30). NO is produced in the endothelium from L-arginine by the enzyme endothelial NO synthase (eNOS) (4, 41) and is released in response to endothelial shear stress and other stimuli such as acetylcholine (4). Wall shear stress (WSS) has also been found to regulate the activity and expression of eNOS (34,40).Oscillatory and reverse WSS have negative effects on the endothelium due to superoxide (O 2 Ϫ ) production (14, 27, 28, 36, 52). It has been found that reverse flow in blood vessels causes reduced NO due to increased O 2 Ϫ production (36). Since NO is atheroprotective, regions of oscillatory and reverse WSS are more prone to atherosclerosis. Regions near branch points and curved vessels produce near-wall reverse flow (15,16).O 2 Ϫ can quickly inactivate NO, causing reduced NO bioavailability and endothelial dysfunction (9, 33). This endothelial dysfunction is implicated in atherosclerosis, hypertension, and heart failure (9,13,14,18,21). Reduced NO in the vessel wall impairs endothelium-dependent vasodilation, decreases inhibition of platelet and leukocyte adhesion, and is linked to the development of intimal hyperplasia (4, 21, 51). Our group has previously shown that NO production is reduced during reverse flow and that the addition of Tempol (an O 2 Ϫ scavenger) restored NO production in reverse flow to...

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Section: Discussionmentioning

confidence: 99%

NADPH oxidase has a directional response to shear stress

Godbole¹,

Lu²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…In other experiments, NDI1 (which encodes the Ndi1 pro-* This work was supported, in whole or in part, by National Institutes of Health Grant R01GM033712 (to T. Yagi). This work was also supported by Japan Society for the Promotion of Science Grant-in-aid for Young Scientists (Start-up) 19870016 (to T. Yamashita) 4 The abbreviations used are: NDH-2, alternative NADH dehydrogenase; complex I, mitochondrial proton-translocating NADH-quinone oxidoreductase; CT, charge transfer; DBQ, n-decylbenzoquinone; DM, dodecyl ␤-Dmaltoside; PpLipDH, lipoamide dehydrogenase of P. putida; Ndi1, internal rotenone-insensitive NADH-ubiquinone oxidoreductase from S. cerevisiae; NQO1, NAD(P)H-quinone oxidoreductase 1 or DT-diaphorase; ROS, reactive oxygen species; DmTR, thioredoxin reductase of D. melanogaster; TX, Triton X-100; UQ, ubiquinone; RB-2, Reactive Blue-2. …”

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confidence: 99%

“…Alternative NADH dehydrogenases (NDH-2) 4 catalyze electron transfer from NADH to quinone without energy transduction. They are commonly found in the respiratory chain of bacteria, fungi, and plant mitochondria but not in mammalian mitochondria (1,2).…”

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confidence: 99%

Reaction Mechanism of Single Subunit NADH-Ubiquinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae

Yu¹,

Yamashita²,

Nakamaru‐Ogiso

et al. 2011

Journal of Biological Chemistry

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The flavoprotein rotenone-insensitive internal NADHubiquinone (UQ) oxidoreductase (Ndi1) is a member of the respiratory chain in Saccharomyces cerevisiae. We reported previously that bound UQ in Ndi1 plays a key role in preventing the generation of reactive oxygen species. Here, to elucidate this mechanism, we investigated biochemical properties of Ndi1 and its mutants in which highly conserved amino acid residues (presumably involved in NADH and/or UQ binding sites) were replaced. We found that wild-type Ndi1 formed a stable charge transfer (CT) complex (around 740 nm) with NADH, but not with NADPH, under anaerobic conditions. The intensity of the CT absorption band was significantly increased by the presence of bound UQ or externally added n-decylbenzoquinone. Interestingly, however, when Ndi1 was exposed to air, the CT band transiently reached the same maximum level regardless of the presence of UQ. This suggests that Ndi1 forms a ternary complex with NADH and UQ, but the role of UQ in withdrawing an electron can be substitutable with oxygen. Proteinase K digestion analysis showed that NADH (but not NADPH) binding induces conformational changes in Ndi1. The kinetic study of wild-type and mutant Ndi1 indicated that there is no overlap between NADH and UQ binding sites. Moreover, we found that the bound UQ can reversibly dissociate from Ndi1 and is thus replaceable with other quinones in the membrane. Taken together, unlike other NAD(P)H-UQ oxidoreductases, the Ndi1 reaction proceeds through a ternary complex (not a ping-pong) mechanism. The bound UQ keeps oxygen away from the reduced flavin. Alternative NADH dehydrogenases (NDH-2)4 catalyze electron transfer from NADH to quinone without energy transduction. They are commonly found in the respiratory chain of bacteria, fungi, and plant mitochondria but not in mammalian mitochondria (1, 2). The NDH-2 enzyme is generally composed of a single polypeptide and can be classified into three groups: A, B, and C. Group A has two adenine dinucleotide (ADP)-binding motifs and is involved in the non-covalent binding of NAD(P)H and FAD. Group B has the same two ADP-binding motifs and an additional conserved EF-hand. Group C has only one conserved ADP-binding motif where flavin is covalently bound (2). The yeast Ndi1 enzyme belongs to group A (2) and catalyzes NADH oxidation on the matrix side of the mitochondrial inner membrane (3) like the energy-transducing NADH dehydrogenase complex I (4).The physiological electron acceptor of NDH-2 is quinone, which is broadly classified into two types: naphthoquinone (menaquinone) and benzoquinone (ubiquinone (UQ)). Ndi1 utilizes the latter as an electron acceptor (2). Both quinones have a hydrophilic head group and hydrophobic isoprenoid side chains and ensure electron transfer between several membrane-bound respiratory enzymes. Ndi1 does not react with oxygen in the presence of UQ. In the absence of quinone, NADH-reduced Ndi1 reacts with oxygen and produces H 2 O 2 , although intrinsic NADH oxidase activity is extremely low (about 30...

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“…1). Lower animals, plants and fungi can use alternative ways to reduce and oxidize CoQ, such as NADH-DH/CoQ reductase activity or CoQ oxidase activity, albeit without proton translocation (2,3). Vertebrate cells lacking a functional mtETC owing to the absence of mtDNA (°cells), can be maintained in culture if supplemented with uridine and pyruvate (4,5).…”

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confidence: 99%

Restoration of electron transport without proton pumping in mammalian mitochondria

Perales‐Clemente

Bayona‐Bafaluy

Pérez‐Martos

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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We have restored the CoQ oxidative capacity of mouse mtDNA-less cells (°cells) by transforming them with the alternative oxidase Aox of Emericella nidulans. Cotransforming °cells with the NADH dehydrogenase of Saccharomyces cerevisiae, Ndi1 and Aox recovered the NADH DH/CoQ reductase and the CoQ oxidase activities. CoQ oxidation by AOX reduces the dependence of °cells on pyruvate and uridine. Coexpression of AOX and NDI1 further improves the recycling of NAD ؉ . Therefore, 2 single-protein enzymes restore the electron transport in mammalian mitochondria substituting >80 nuclear DNA-encoded and 11 mtDNA-encoded proteins. Because those enzymes do not pump protons, we were able to split electron transport and proton pumping (ATP synthesis) and inquire which of the metabolic deficiencies associated with the loss of oxidative phosphorylation should be attributed to each of the 2 processes.AOX ͉ mouse ͉ oxidative phosphorylation ͉ NDI1 ͉ CoQ

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Can a Single Subunit Yeast NADH Dehydrogenase (Ndi1) Remedy Diseases Caused by Respiratory Complex I Defects?

Cited by 40 publications

References 32 publications

NADPH oxidase has a directional response to shear stress

NADPH oxidase has a directional response to shear stress

Reaction Mechanism of Single Subunit NADH-Ubiquinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae

Restoration of electron transport without proton pumping in mammalian mitochondria

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