Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo
Identifieur interne : 001741 ( Ncbi/Merge ); précédent : 001740; suivant : 001742Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo
Auteurs : Hyung-Wook Kim [États-Unis, Corée du Sud] ; Won-Seok Choi [États-Unis, Corée du Sud] ; Noah Sorscher [États-Unis] ; Hyung Joon Park [Corée du Sud] ; François Tronche [France] ; Richard D. Palmiter [États-Unis] ; Zhengui Xia [États-Unis]Source :
- Neurobiology of aging [ 0197-4580 ] ; 2015.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology), Age Factors, Animals, Antigens, Neoplasm (genetics), Antigens, Neoplasm (metabolism), Dopamine (metabolism), Dopamine Agents (pharmacology), Dopamine Plasma Membrane Transport Proteins (metabolism), Dopaminergic Neurons (drug effects), Dopaminergic Neurons (metabolism), Dopaminergic Neurons (ultrastructure), Dose-Response Relationship, Drug, Electron Transport Complex I (deficiency), Electron Transport Complex I (genetics), Exploratory Behavior (drug effects), Exploratory Behavior (physiology), Gene Expression Regulation (drug effects), Gene Expression Regulation (genetics), Levodopa (pharmacology), Male, Mice, Mice, Knockout, Mitochondria (drug effects), Mitochondria (metabolism), Motor Activity (drug effects), Motor Activity (genetics), Oxygen Consumption (drug effects), Oxygen Consumption (genetics), Psychomotor Performance (drug effects), Psychomotor Performance (physiology), Substantia Nigra (cytology), Substantia Nigra (drug effects), Synaptosomes (drug effects), Synaptosomes (metabolism), Tyrosine 3-Monooxygenase (metabolism).
- MESH :
- chemical , deficiency : Electron Transport Complex I.
- chemical , genetics : Antigens, Neoplasm, Electron Transport Complex I.
- chemical , metabolism : Antigens, Neoplasm, Dopamine, Dopamine Plasma Membrane Transport Proteins, Tyrosine 3-Monooxygenase.
- chemical , pharmacology : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Dopamine Agents, Levodopa.
- cytology : Substantia Nigra.
- drug effects : Dopaminergic Neurons, Exploratory Behavior, Gene Expression Regulation, Mitochondria, Motor Activity, Oxygen Consumption, Psychomotor Performance, Substantia Nigra, Synaptosomes.
- genetics : Gene Expression Regulation, Motor Activity, Oxygen Consumption.
- metabolism : Dopaminergic Neurons, Mitochondria, Synaptosomes.
- physiology : Exploratory Behavior, Psychomotor Performance.
- ultrastructure : Dopaminergic Neurons.
- Age Factors, Animals, Dose-Response Relationship, Drug, Male, Mice, Mice, Knockout.
Abstract
Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson’s disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 cKO) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and upon MPTP treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the SNpc or dopamine-dependent motor deficits over the 24-month lifespan. These mice were just as susceptible to MPTP as control mice. However, compared to control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the SNpc. We also utilized an inducible Ndufs4 knockout mouse strain (Ndufs4 iKO) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 iKO mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell- autonomous dopaminergic neuron death during the normal lifespan of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or non-autonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson’s disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.
Url:
DOI: 10.1016/j.neurobiolaging.2015.05.008
PubMed: 26070241
PubMed Central: 4523431
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<front><div type="abstract" xml:lang="en"><p id="P2">Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson’s disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 cKO) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and upon MPTP treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the SNpc or dopamine-dependent motor deficits over the 24-month lifespan. These mice were just as susceptible to MPTP as control mice. However, compared to control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the SNpc. We also utilized an inducible Ndufs4 knockout mouse strain (Ndufs4 iKO) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 iKO mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell- autonomous dopaminergic neuron death during the normal lifespan of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or non-autonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson’s disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.</p>
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<front><div type="abstract" xml:lang="en"><p id="P2">Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson’s disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 cKO) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and upon MPTP treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the SNpc or dopamine-dependent motor deficits over the 24-month lifespan. These mice were just as susceptible to MPTP as control mice. However, compared to control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the SNpc. We also utilized an inducible Ndufs4 knockout mouse strain (Ndufs4 iKO) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 iKO mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell- autonomous dopaminergic neuron death during the normal lifespan of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or non-autonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson’s disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.</p>
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<author><name sortKey="Xia, Zhengui" sort="Xia, Zhengui" uniqKey="Xia Z" first="Zhengui" last="Xia">Zhengui Xia</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo.</title>
<author><name sortKey="Kim, Hyung Wook" sort="Kim, Hyung Wook" uniqKey="Kim H" first="Hyung-Wook" last="Kim">Hyung-Wook Kim</name>
<affiliation wicri:level="4"><nlm:affiliation>Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; College of Life Sciences, Sejong University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; College of Life Sciences, Sejong University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author><name sortKey="Choi, Won Seok" sort="Choi, Won Seok" uniqKey="Choi W" first="Won-Seok" last="Choi">Won-Seok Choi</name>
<affiliation wicri:level="4"><nlm:affiliation>Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sorscher, Noah" sort="Sorscher, Noah" uniqKey="Sorscher N" first="Noah" last="Sorscher">Noah Sorscher</name>
<affiliation wicri:level="4"><nlm:affiliation>Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA</wicri:regionArea>
<placeName><region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author><name sortKey="Park, Hyung Joon" sort="Park, Hyung Joon" uniqKey="Park H" first="Hyung Joon" last="Park">Hyung Joon Park</name>
<affiliation wicri:level="1"><nlm:affiliation>School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju</wicri:regionArea>
<wicri:noRegion>Gwangju</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tronche, Francois" sort="Tronche, Francois" uniqKey="Tronche F" first="François" last="Tronche">François Tronche</name>
<affiliation wicri:level="3"><nlm:affiliation>Sorbonne Universités, Université Pierre et Marie Curie, UMR_CR18, Neuroscience Paris-Seine, Paris, France; Centre National de la Recherche Scientifique UMR 8246, Paris, France; Institut National de la Santé et de la Rechesrche Médicale U1130, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Sorbonne Universités, Université Pierre et Marie Curie, UMR_CR18, Neuroscience Paris-Seine, Paris, France; Centre National de la Recherche Scientifique UMR 8246, Paris, France; Institut National de la Santé et de la Rechesrche Médicale U1130, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Palmiter, Richard D" sort="Palmiter, Richard D" uniqKey="Palmiter R" first="Richard D" last="Palmiter">Richard D. Palmiter</name>
<affiliation wicri:level="4"><nlm:affiliation>Howard Huges Medical Institute, University of Washington, Seattle, WA, USA; Department of Biochemistry, University of Washington, Seattle, WA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Howard Huges Medical Institute, University of Washington, Seattle, WA, USA; Department of Biochemistry, University of Washington, Seattle, WA</wicri:regionArea>
<placeName><region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author><name sortKey="Xia, Zhengui" sort="Xia, Zhengui" uniqKey="Xia Z" first="Zhengui" last="Xia">Zhengui Xia</name>
<affiliation wicri:level="4"><nlm:affiliation>Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA, USA. Electronic address: zxia@uw.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA</wicri:regionArea>
<placeName><region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
</analytic>
<series><title level="j">Neurobiology of aging</title>
<idno type="eISSN">1558-1497</idno>
<imprint><date when="2015" type="published">2015</date>
</imprint>
</series>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)</term>
<term>Age Factors</term>
<term>Animals</term>
<term>Antigens, Neoplasm (genetics)</term>
<term>Antigens, Neoplasm (metabolism)</term>
<term>Dopamine (metabolism)</term>
<term>Dopamine Agents (pharmacology)</term>
<term>Dopamine Plasma Membrane Transport Proteins (metabolism)</term>
<term>Dopaminergic Neurons (drug effects)</term>
<term>Dopaminergic Neurons (metabolism)</term>
<term>Dopaminergic Neurons (ultrastructure)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Electron Transport Complex I (deficiency)</term>
<term>Electron Transport Complex I (genetics)</term>
<term>Exploratory Behavior (drug effects)</term>
<term>Exploratory Behavior (physiology)</term>
<term>Gene Expression Regulation (drug effects)</term>
<term>Gene Expression Regulation (genetics)</term>
<term>Levodopa (pharmacology)</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Mitochondria (drug effects)</term>
<term>Mitochondria (metabolism)</term>
<term>Motor Activity (drug effects)</term>
<term>Motor Activity (genetics)</term>
<term>Oxygen Consumption (drug effects)</term>
<term>Oxygen Consumption (genetics)</term>
<term>Psychomotor Performance (drug effects)</term>
<term>Psychomotor Performance (physiology)</term>
<term>Substantia Nigra (cytology)</term>
<term>Substantia Nigra (drug effects)</term>
<term>Synaptosomes (drug effects)</term>
<term>Synaptosomes (metabolism)</term>
<term>Tyrosine 3-Monooxygenase (metabolism)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Electron Transport Complex I</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antigens, Neoplasm</term>
<term>Electron Transport Complex I</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antigens, Neoplasm</term>
<term>Dopamine</term>
<term>Dopamine Plasma Membrane Transport Proteins</term>
<term>Tyrosine 3-Monooxygenase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term>
<term>Dopamine Agents</term>
<term>Levodopa</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Substantia Nigra</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Dopaminergic Neurons</term>
<term>Exploratory Behavior</term>
<term>Gene Expression Regulation</term>
<term>Mitochondria</term>
<term>Motor Activity</term>
<term>Oxygen Consumption</term>
<term>Psychomotor Performance</term>
<term>Substantia Nigra</term>
<term>Synaptosomes</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Gene Expression Regulation</term>
<term>Motor Activity</term>
<term>Oxygen Consumption</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Dopaminergic Neurons</term>
<term>Mitochondria</term>
<term>Synaptosomes</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Exploratory Behavior</term>
<term>Psychomotor Performance</term>
</keywords>
<keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Dopaminergic Neurons</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Age Factors</term>
<term>Animals</term>
<term>Dose-Response Relationship, Drug</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Knockout</term>
</keywords>
</textClass>
</profileDesc>
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<front><div type="abstract" xml:lang="en">Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson's disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.</div>
</front>
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