PittsburghV1, Main, Exploration, bibRecord, 002666

Inhibition of mitochondrial protein import by mutant huntingtin

Identifieur interne : 002666 ( Main/Exploration ); précédent : 002665; suivant : 002667

Inhibition of mitochondrial protein import by mutant huntingtin

Auteurs : Hiroko Yano [États-Unis] ; Sergei V. Baranov [États-Unis] ; Oxana V. Baranova [États-Unis] ; Jinho Kim [États-Unis] ; Yanchun Pan [États-Unis] ; Svitlana Yablonska [États-Unis] ; Diane L. Carlisle [États-Unis] ; Robert J. Ferrante [États-Unis] ; Albert H. Kim [États-Unis] ; Robert M. Friedlander [États-Unis]

Source :

Nature neuroscience [ 1097-6256 ] ; 2014.

RBID : PMC:4174557

Descripteurs français

KwdFr :
- Adulte d'âge moyen, Animaux, Cellules HEK293, Cellules cultivées, Femelle, Humains, Maladie de Huntington (), Maladie de Huntington (anatomopathologie), Maladie de Huntington (génétique), Mitochondries (anatomopathologie), Mitochondries (génétique), Mitochondries (métabolisme), Mutation, Mâle, Protéine huntingtine, Protéines de tissu nerveux (génétique), Protéines de tissu nerveux (physiologie), Protéines mitochondriales (antagonistes et inhibiteurs), Protéines mitochondriales (génétique), Protéines mitochondriales (métabolisme), Souris, Souris de lignée CBA, Souris transgéniques, Sujet âgé, Transport de protéines (génétique).
MESH :
- anatomopathologie : Maladie de Huntington, Mitochondries.
- antagonistes et inhibiteurs : Protéines mitochondriales.
- génétique : Maladie de Huntington, Mitochondries, Protéines de tissu nerveux, Protéines mitochondriales, Transport de protéines.
- métabolisme : Mitochondries, Protéines mitochondriales.
- physiologie : Protéines de tissu nerveux.
- Adulte d'âge moyen, Animaux, Cellules HEK293, Cellules cultivées, Femelle, Humains, Maladie de Huntington, Mutation, Mâle, Protéine huntingtine, Souris, Souris de lignée CBA, Souris transgéniques, Sujet âgé.

English descriptors

KwdEn :
- Aged, Animals, Cells, Cultured, Female, HEK293 Cells, Humans, Huntingtin Protein, Huntington Disease (genetics), Huntington Disease (pathology), Huntington Disease (therapy), Male, Mice, Mice, Inbred CBA, Mice, Transgenic, Middle Aged, Mitochondria (genetics), Mitochondria (metabolism), Mitochondria (pathology), Mitochondrial Proteins (antagonists & inhibitors), Mitochondrial Proteins (genetics), Mitochondrial Proteins (metabolism), Mutation, Nerve Tissue Proteins (genetics), Nerve Tissue Proteins (physiology), Protein Transport (genetics).
MESH :
- chemical , antagonists & inhibitors : Mitochondrial Proteins.
- chemical , genetics : Mitochondrial Proteins, Nerve Tissue Proteins.
- chemical , metabolism : Mitochondrial Proteins.
- chemical , physiology : Nerve Tissue Proteins.
- chemical : Huntingtin Protein.
- genetics : Huntington Disease, Mitochondria, Protein Transport.
- metabolism : Mitochondria.
- pathology : Huntington Disease, Mitochondria.
- therapy : Huntington Disease.
- Aged, Animals, Cells, Cultured, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred CBA, Mice, Transgenic, Middle Aged, Mutation.

Abstract

Mitochondrial dysfunction is associated with neuronal loss in Huntington’s disease (HD), a neurodegenerative disease caused by an abnormal polyglutamine expansion in huntingtin (Htt). However, the mechanisms linking mutant Htt and mitochondrial dysfunction in HD remain unknown. We identify an interaction between mutant Htt and the TIM23 mitochondrial protein import complex. Remarkably, recombinant mutant Htt directly inhibited mitochondrial protein import in vitro. Furthermore, mitochondria from brain synaptosomes of presymptomatic HD model mice and from mutant Htt-expressing primary neurons exhibited a protein import defect, suggesting that deficient protein import is an early event in HD. The mutant Htt-induced mitochondrial import defect and subsequent neuronal death were attenuated by overexpression of TIM23 complex subunits, demonstrating that deficient mitochondrial protein import causes mutant Htt-induced neuronal death. Collectively, these findings provide evidence for a direct link between mutant Htt, mitochondrial dysfunction and neuronal pathology, with implications for mitochondrial protein import-based therapies in HD.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174557

DOI: 10.1038/nn.3721
PubMed: 24836077
PubMed Central: 4174557

Affiliations:

Le document en format XML

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<author><name sortKey="Baranova, Oxana V" sort="Baranova, Oxana V" uniqKey="Baranova O" first="Oxana V" last="Baranova">Oxana V. Baranova</name>
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<author><name sortKey="Yablonska, Svitlana" sort="Yablonska, Svitlana" uniqKey="Yablonska S" first="Svitlana" last="Yablonska">Svitlana Yablonska</name>
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<author><name sortKey="Carlisle, Diane L" sort="Carlisle, Diane L" uniqKey="Carlisle D" first="Diane L" last="Carlisle">Diane L. Carlisle</name>
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<author><name sortKey="Ferrante, Robert J" sort="Ferrante, Robert J" uniqKey="Ferrante R" first="Robert J" last="Ferrante">Robert J. Ferrante</name>
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<author><name sortKey="Kim, Albert H" sort="Kim, Albert H" uniqKey="Kim A" first="Albert H" last="Kim">Albert H. Kim</name>
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</placeName>
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<affiliation wicri:level="4"><nlm:aff id="A3">Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Washington University School of Medicine, St. Louis, Missouri</wicri:regionArea>
<placeName><region type="state">Missouri (État)</region>
<settlement type="city">Saint-Louis (Missouri)</settlement>
</placeName>
<orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="A5">Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Friedlander, Robert M" sort="Friedlander, Robert M" uniqKey="Friedlander R" first="Robert M" last="Friedlander">Robert M. Friedlander</name>
<affiliation wicri:level="4"><nlm:aff id="A1">Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh, Pittsburgh, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurological Surgery, Neuroapoptosis Laboratory, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A6">University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature neuroscience</title>
<idno type="ISSN">1097-6256</idno>
<idno type="eISSN">1546-1726</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term>
<term>Animals</term>
<term>Cells, Cultured</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>Humans</term>
<term>Huntingtin Protein</term>
<term>Huntington Disease (genetics)</term>
<term>Huntington Disease (pathology)</term>
<term>Huntington Disease (therapy)</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred CBA</term>
<term>Mice, Transgenic</term>
<term>Middle Aged</term>
<term>Mitochondria (genetics)</term>
<term>Mitochondria (metabolism)</term>
<term>Mitochondria (pathology)</term>
<term>Mitochondrial Proteins (antagonists & inhibitors)</term>
<term>Mitochondrial Proteins (genetics)</term>
<term>Mitochondrial Proteins (metabolism)</term>
<term>Mutation</term>
<term>Nerve Tissue Proteins (genetics)</term>
<term>Nerve Tissue Proteins (physiology)</term>
<term>Protein Transport (genetics)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Adulte d'âge moyen</term>
<term>Animaux</term>
<term>Cellules HEK293</term>
<term>Cellules cultivées</term>
<term>Femelle</term>
<term>Humains</term>
<term>Maladie de Huntington ()</term>
<term>Maladie de Huntington (anatomopathologie)</term>
<term>Maladie de Huntington (génétique)</term>
<term>Mitochondries (anatomopathologie)</term>
<term>Mitochondries (génétique)</term>
<term>Mitochondries (métabolisme)</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Protéine huntingtine</term>
<term>Protéines de tissu nerveux (génétique)</term>
<term>Protéines de tissu nerveux (physiologie)</term>
<term>Protéines mitochondriales (antagonistes et inhibiteurs)</term>
<term>Protéines mitochondriales (génétique)</term>
<term>Protéines mitochondriales (métabolisme)</term>
<term>Souris</term>
<term>Souris de lignée CBA</term>
<term>Souris transgéniques</term>
<term>Sujet âgé</term>
<term>Transport de protéines (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Mitochondrial Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Mitochondrial Proteins</term>
<term>Nerve Tissue Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Mitochondrial Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Nerve Tissue Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en"><term>Huntingtin Protein</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Maladie de Huntington</term>
<term>Mitochondries</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines mitochondriales</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Huntington Disease</term>
<term>Mitochondria</term>
<term>Protein Transport</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Maladie de Huntington</term>
<term>Mitochondries</term>
<term>Protéines de tissu nerveux</term>
<term>Protéines mitochondriales</term>
<term>Transport de protéines</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Mitochondries</term>
<term>Protéines mitochondriales</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Huntington Disease</term>
<term>Mitochondria</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Protéines de tissu nerveux</term>
</keywords>
<keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Huntington Disease</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Aged</term>
<term>Animals</term>
<term>Cells, Cultured</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred CBA</term>
<term>Mice, Transgenic</term>
<term>Middle Aged</term>
<term>Mutation</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Adulte d'âge moyen</term>
<term>Animaux</term>
<term>Cellules HEK293</term>
<term>Cellules cultivées</term>
<term>Femelle</term>
<term>Humains</term>
<term>Maladie de Huntington</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Protéine huntingtine</term>
<term>Souris</term>
<term>Souris de lignée CBA</term>
<term>Souris transgéniques</term>
<term>Sujet âgé</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">Mitochondrial dysfunction is associated with neuronal loss in Huntington’s disease (HD), a neurodegenerative disease caused by an abnormal polyglutamine expansion in huntingtin (Htt). However, the mechanisms linking mutant Htt and mitochondrial dysfunction in HD remain unknown. We identify an interaction between mutant Htt and the TIM23 mitochondrial protein import complex. Remarkably, recombinant mutant Htt directly inhibited mitochondrial protein import <italic>in vitro</italic>
. Furthermore, mitochondria from brain synaptosomes of presymptomatic HD model mice and from mutant Htt-expressing primary neurons exhibited a protein import defect, suggesting that deficient protein import is an early event in HD. The mutant Htt-induced mitochondrial import defect and subsequent neuronal death were attenuated by overexpression of TIM23 complex subunits, demonstrating that deficient mitochondrial protein import causes mutant Htt-induced neuronal death. Collectively, these findings provide evidence for a direct link between mutant Htt, mitochondrial dysfunction and neuronal pathology, with implications for mitochondrial protein import-based therapies in HD.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Missouri (État)</li>
<li>Pennsylvanie</li>
</region>
<settlement><li>Pittsburgh</li>
<li>Saint-Louis (Missouri)</li>
</settlement>
<orgName><li>Université de Pittsburgh</li>
<li>École de médecine (Université Washington de Saint-Louis)</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Yano, Hiroko" sort="Yano, Hiroko" uniqKey="Yano H" first="Hiroko" last="Yano">Hiroko Yano</name>
</region>
<name sortKey="Baranov, Sergei V" sort="Baranov, Sergei V" uniqKey="Baranov S" first="Sergei V" last="Baranov">Sergei V. Baranov</name>
<name sortKey="Baranova, Oxana V" sort="Baranova, Oxana V" uniqKey="Baranova O" first="Oxana V" last="Baranova">Oxana V. Baranova</name>
<name sortKey="Carlisle, Diane L" sort="Carlisle, Diane L" uniqKey="Carlisle D" first="Diane L" last="Carlisle">Diane L. Carlisle</name>
<name sortKey="Ferrante, Robert J" sort="Ferrante, Robert J" uniqKey="Ferrante R" first="Robert J" last="Ferrante">Robert J. Ferrante</name>
<name sortKey="Friedlander, Robert M" sort="Friedlander, Robert M" uniqKey="Friedlander R" first="Robert M" last="Friedlander">Robert M. Friedlander</name>
<name sortKey="Friedlander, Robert M" sort="Friedlander, Robert M" uniqKey="Friedlander R" first="Robert M" last="Friedlander">Robert M. Friedlander</name>
<name sortKey="Kim, Albert H" sort="Kim, Albert H" uniqKey="Kim A" first="Albert H" last="Kim">Albert H. Kim</name>
<name sortKey="Kim, Albert H" sort="Kim, Albert H" uniqKey="Kim A" first="Albert H" last="Kim">Albert H. Kim</name>
<name sortKey="Kim, Albert H" sort="Kim, Albert H" uniqKey="Kim A" first="Albert H" last="Kim">Albert H. Kim</name>
<name sortKey="Kim, Jinho" sort="Kim, Jinho" uniqKey="Kim J" first="Jinho" last="Kim">Jinho Kim</name>
<name sortKey="Pan, Yanchun" sort="Pan, Yanchun" uniqKey="Pan Y" first="Yanchun" last="Pan">Yanchun Pan</name>
<name sortKey="Yablonska, Svitlana" sort="Yablonska, Svitlana" uniqKey="Yablonska S" first="Svitlana" last="Yablonska">Svitlana Yablonska</name>
<name sortKey="Yano, Hiroko" sort="Yano, Hiroko" uniqKey="Yano H" first="Hiroko" last="Yano">Hiroko Yano</name>
<name sortKey="Yano, Hiroko" sort="Yano, Hiroko" uniqKey="Yano H" first="Hiroko" last="Yano">Hiroko Yano</name>
<name sortKey="Yano, Hiroko" sort="Yano, Hiroko" uniqKey="Yano H" first="Hiroko" last="Yano">Hiroko Yano</name>
</country>
</tree>
</affiliations>
</record>

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Inhibition of mitochondrial protein import by mutant huntingtin

Inhibition of mitochondrial protein import by mutant huntingtin

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