Obligatory Role for Complex I Inhibition in the Dopaminergic Neurotoxicity of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Richardson, Jason R.; Caudle, W. Michael; Guillot, Thomas S.; Watson, Jodi L.; Nakamaru‐Ogiso, Eiko; Seo, Byoung Boo; Sherer, Todd; Greenamyre, J. Timothy; Yagi, Takao; Matsuno‐Yagi, Akemi; Miller, Gary W.

doi:10.1093/toxsci/kfl133

Cited by 108 publications

(87 citation statements)

References 41 publications

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“…We have demonstrated that the Ndi1 can be introduced into mammalian mitochondria as an alternative NADH dehydrogenase for the respiratory chain and is able to complement defective complex I both in cultured cells and in animals (5,8,12,14). Successful incorporation of the Ndi1 with the bovine inner mitochondrial membrane in vitro should provide us a powerful model in which to investigate FIGURE 7.…”

Section: Methodsmentioning

confidence: 99%

“…In fact, the Ndi1 expression in the substantia nigra of mouse brains has protective effects against Parkinsonian symptoms caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (12,14). Recently, we illustrated that the expressed Ndi1 enzyme may play a dual role in rescuing complex I-deficient cells (15); one is to restore the NADH oxidase activity, and the other is to decrease oxidative damage by complex I inhibition.…”

Section: Alternative Nadh Dehydrogenases (Ndh-2)mentioning

confidence: 99%

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Roles of Bound Quinone in the Single Subunit NADH-Quinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae

Yamashita

Nakamaru‐Ogiso

Miyoshi

et al. 2007

Journal of Biological Chemistry

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To understand the biochemical basis for the function of the rotenone-insensitive internal NADH-quinone (Q) oxidoreductase (Ndi1), we have overexpressed mature Ndi1 in Escherichia coli membranes. The Ndi1 purified from the membranes contained one FAD and showed enzymatic activities comparable with the original Ndi1 isolated from Saccharomyces cerevisiae. When extracted with Triton X-100, the isolated Ndi1 did not contain Q. The Q-bound form was easily reconstituted by incubation of the Q-free Ndi1 enzyme with ubiquinone-6. We compared the properties of Q-bound Ndi1 enzyme with those of Q-free Ndi1 enzyme, with higher activity found in the Q-bound enzyme. Although both are inhibited by low concentrations of AC0 -11 (IC 50 ‫؍‬ 0.2 M), the inhibitory mode of AC0 -11 on Q-bound Ndi1 was distinct from that of Q-free Ndi1. The bound Q was slowly released from Ndi1 by treatment with NADH or dithionite under anaerobic conditions. This release of Q was prevented when Ndi1 was kept in the reduced state by NADH. When Ndi1 was incorporated into bovine heart submitochondrial particles, the Q-bound form, but not the Q-free form, established the NADH-linked respiratory activity, which was insensitive to piericidin A but inhibited by KCN. Furthermore, Ndi1 produces H 2 O 2 as isolated regardless of the presence of bound Q, and this H 2 O 2 was eliminated when the Q-bound Ndi1, but not the Q-free Ndi1, was incorporated into submitochondrial particles. The data suggest that Ndi1 bears at least two distinct Q sites: one for bound Q and the other for catalytic Q. Alternative NADH dehydrogenases (NDH-2)3 catalyze electron transfer from NADH to quinone (Q) without the energy transduction. NDH-2 is considered to be composed of a single polypeptide, houses FAD as a cofactor (1, 2) and is regarded to have the simplest structure among the NADH dehydrogenases (2). The NDH-2 enzymes are present in bacteria, plant, and fungal mitochondria but not in mammalian mitochondria. In bacteria, all NDH-2 enzymes known to date are located in the cytoplasmic phase. By contrast, plant and fungal mitochondria possess two types of NDH-2 enzymes (3); one is directed to the matrix and catalyzes NADH oxidation in the matrix (designated the internal NADH dehydrogenase or Ndi), whereas the other faces the intermembrane space and oxidizes NADH in the cytoplasmic space (designated the external NADH dehydrogenases or Nde). The Ndi1 enzyme is similar to complex I in terms of NADH oxidation in the matrix (4).A series of studies in our laboratory suggest that the Saccharomyces cerevisiae NDI1 gene may work as a therapeutic agent for mitochondrial diseases caused by complex I deficiencies (5-13). In fact, the Ndi1 expression in the substantia nigra of mouse brains has protective effects against Parkinsonian symptoms caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (12,14). Recently, we illustrated that the expressed Ndi1 enzyme may play a dual role in rescuing complex I-deficient cells (15); one is to restore the NADH oxidase activity, and the other i...

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Section: Methodsmentioning

confidence: 99%

Section: Alternative Nadh Dehydrogenases (Ndh-2)mentioning

confidence: 99%

Roles of Bound Quinone in the Single Subunit NADH-Quinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae

Yamashita

Nakamaru‐Ogiso

Miyoshi

et al. 2007

Journal of Biological Chemistry

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“…We also treated neurons with MPPϩ the active metabolite of the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that is known to cause Parkinson's syndrome in rodents and humans (Przedborski and Ischiropoulos, 2005). MPPϩ is an inhibitor of the respiratory chain complex-I and its toxicity has been shown to be caused by the consequent production of oxygen derived free radicals (Fallon et al, 1997;Przedborski and Ischiropoulos, 2005;Richardson et al, 2007). All of these oxidative stressors triggered a significant increase in the fraction of cells exhibiting an apoptotic nuclear morphology characterized by chromatin condensation and/or nuclear fragmentation (Fig.…”

Section: Oxidative Damage Triggers Neuronal Apoptosis Through a Mitocmentioning

confidence: 99%

Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal Apoptosis

Steckley¹,

Karajgikar²,

Dale³

et al. 2007

J. Neurosci.

129

144

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Oxidative stress has been implicated as a key trigger of neuronal apoptosis in stroke and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The Bcl-2 homology 3 (BH3)-only subfamily of Bcl-2 genes consists of multiple members that can be activated in a cell-type-and stimulus-specific manner to promote cell death. In the present study, we demonstrate that, in cortical neurons, oxidative stress induces the expression of the BH3-only members Bim, Noxa, and Puma. Importantly, we have determined that Puma؊/؊ neurons, but not Bim؊/؊ or Noxa؊/؊ neurons, are remarkably resistant to the induction of apoptosis by multiple oxidative stressors. Furthermore, we have determined that Bcl-2-associated X protein (Bax) is also required for oxidative stress induced cell death and that Puma plays a dominant role in regulating Bax activation. Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization. Finally, we demonstrate that whereas both Puma and Bim EL can bind to the antiapoptotic family member Bcl-X L , only Puma was found to associate with Bax. This suggests that in addition to neutralizing antiapoptotic members, Puma may play a dominant role by complexing with Bax and directly promoting its activation. Overall, we have identified Puma as a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis, and suggest that Puma may be an effective therapeutic target for the treatment of a number of neurodegenerative conditions.

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“…1), which is then taken up by neurons of the substantia nigra via the dopamine transporter [3]. In cells, MPP ϩ accumulates in mitochondria and binds to complex I of the electron transport chain, resulting in the production of reactive oxygen species (ROS) by the organelle, a decline in ATP biosynthesis, and eventually the demise of the cells [6,7]. A few insecticides and herbicides that also target mitochondrial complex I have been demonstrated to induce Parkinsonism in animal models, supporting the role of environmental toxins in the neurodegeneration [4].…”

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confidence: 99%

Neoechinulin A Protects PC12 Cells against MPP+-induced Cytotoxicity

et al. 2008

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Neoechinulin A, an alkaloid from Eurotium rubrum, can protect neuronal PC12 cells against cytotoxicity of a potent oxidant, peroxynitrite. Because involvement of peroxynitrite has been suggested in the pathogenesis of Parkinson's disease, we assessed whether this alkaloid could also protect PC12 cells from the cytocidal action of 1-methyl-4-phenylpyridine (MPP ϩ ), a Parkinson's disease, which affects 0.1% of the population over the age of 40 years, is characterized by a progressive loss of dopaminergic neurons in the substantia nigra [3,4]. Currently, no cure is available that can impede neuronal cell death. Except for some inherited cases, causative factors for the vast majority of cases remain elusive. The environmental toxin hypothesis has gained attention since the identification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a by-product of illegal heroin synthesis, as a causative agent for an acute Parkinson's-like disorder among drug abusers [5]. In the brain, MPTP is oxidized to 1-methyl-4-phenylpyridine (MPP ϩ ; Fig. 1), which is then taken up by neurons of the substantia nigra via the dopamine transporter [3]. In cells, MPP ϩ accumulates in mitochondria and binds to complex I of the electron transport chain, resulting in the production of reactive oxygen species (ROS) by the organelle, a decline in ATP biosynthesis, and eventually the demise of the cells [6,7]. A few insecticides and herbicides that also target mitochondrial complex I have been demonstrated to induce Parkinsonism in animal models, supporting the role of environmental toxins in the neurodegeneration [4]. MPTP and MPP ϩ have been widely used in studies of Parkinson's disease in rodents and in cultured cells, respectively. As peroxynitrite has been suggested to be involved in the pathogenesis of Parkinson's disease as well as MPP ϩ cytotoxicity in animals and cultured cells [3,8,9], we

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Obligatory Role for Complex I Inhibition in the Dopaminergic Neurotoxicity of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Cited by 108 publications

References 41 publications

Roles of Bound Quinone in the Single Subunit NADH-Quinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae

Roles of Bound Quinone in the Single Subunit NADH-Quinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae

Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal Apoptosis

Neoechinulin A Protects PC12 Cells against MPP+-induced Cytotoxicity

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