La maladie de Parkinson au Canada (serveur d'exploration)

Attention, ce site est en cours de développement !
Attention, site généré par des moyens informatiques à partir de corpus bruts.
Les informations ne sont donc pas validées.

Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin

Identifieur interne : 000D31 ( Main/Exploration ); précédent : 000D30; suivant : 000D32

Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin

Auteurs : Poonam Bhandari ; Moshi Song ; Yun Chen ; Yan Burelle ; Gerald W. Dorn

Source :

RBID : PMC:4392818

English descriptors

Abstract

Rationale

Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood.

Objective

We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in Drosophila heart tubes.

Methods and Results

Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because Drosophila lack most of these redundant genes, we examined heart tubes of parkin knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy.

Conclusions

Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by inhibiting organelle fusion shows promise for minimizing organ dysfunction produced by defective mitophagic signaling.


Url:
DOI: 10.1161/CIRCRESAHA.114.302734
PubMed: 24192653
PubMed Central: 4392818


Affiliations:


Links toward previous steps (curation, corpus...)


Le document en format XML

<record>
<TEI>
<teiHeader>
<fileDesc>
<titleStmt>
<title xml:lang="en">Mitochondrial Contagion Induced by Parkin Deficiency in
<italic>Drosophila</italic>
Hearts and Its Containment by Suppressing Mitofusin</title>
<author>
<name sortKey="Bhandari, Poonam" sort="Bhandari, Poonam" uniqKey="Bhandari P" first="Poonam" last="Bhandari">Poonam Bhandari</name>
</author>
<author>
<name sortKey="Song, Moshi" sort="Song, Moshi" uniqKey="Song M" first="Moshi" last="Song">Moshi Song</name>
</author>
<author>
<name sortKey="Chen, Yun" sort="Chen, Yun" uniqKey="Chen Y" first="Yun" last="Chen">Yun Chen</name>
</author>
<author>
<name sortKey="Burelle, Yan" sort="Burelle, Yan" uniqKey="Burelle Y" first="Yan" last="Burelle">Yan Burelle</name>
</author>
<author>
<name sortKey="Dorn, Gerald W" sort="Dorn, Gerald W" uniqKey="Dorn G" first="Gerald W." last="Dorn">Gerald W. Dorn</name>
</author>
</titleStmt>
<publicationStmt>
<idno type="wicri:source">PMC</idno>
<idno type="pmid">24192653</idno>
<idno type="pmc">4392818</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392818</idno>
<idno type="RBID">PMC:4392818</idno>
<idno type="doi">10.1161/CIRCRESAHA.114.302734</idno>
<date when="2013">2013</date>
<idno type="wicri:Area/Pmc/Corpus">000698</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000698</idno>
<idno type="wicri:Area/Pmc/Curation">000698</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000698</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000625</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000625</idno>
<idno type="wicri:source">PubMed</idno>
<idno type="wicri:Area/PubMed/Corpus">000798</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000798</idno>
<idno type="wicri:Area/PubMed/Curation">000798</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000798</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000798</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000798</idno>
<idno type="wicri:Area/Ncbi/Merge">001606</idno>
<idno type="wicri:Area/Ncbi/Curation">001606</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">001606</idno>
<idno type="wicri:doubleKey">0009-7330:2013:Bhandari P:mitochondrial:contagion:induced</idno>
<idno type="wicri:Area/Main/Merge">000D42</idno>
<idno type="wicri:Area/Main/Curation">000D31</idno>
<idno type="wicri:Area/Main/Exploration">000D31</idno>
</publicationStmt>
<sourceDesc>
<biblStruct>
<analytic>
<title xml:lang="en" level="a" type="main">Mitochondrial Contagion Induced by Parkin Deficiency in
<italic>Drosophila</italic>
Hearts and Its Containment by Suppressing Mitofusin</title>
<author>
<name sortKey="Bhandari, Poonam" sort="Bhandari, Poonam" uniqKey="Bhandari P" first="Poonam" last="Bhandari">Poonam Bhandari</name>
</author>
<author>
<name sortKey="Song, Moshi" sort="Song, Moshi" uniqKey="Song M" first="Moshi" last="Song">Moshi Song</name>
</author>
<author>
<name sortKey="Chen, Yun" sort="Chen, Yun" uniqKey="Chen Y" first="Yun" last="Chen">Yun Chen</name>
</author>
<author>
<name sortKey="Burelle, Yan" sort="Burelle, Yan" uniqKey="Burelle Y" first="Yan" last="Burelle">Yan Burelle</name>
</author>
<author>
<name sortKey="Dorn, Gerald W" sort="Dorn, Gerald W" uniqKey="Dorn G" first="Gerald W." last="Dorn">Gerald W. Dorn</name>
</author>
</analytic>
<series>
<title level="j">Circulation research</title>
<idno type="ISSN">0009-7330</idno>
<idno type="eISSN">1524-4571</idno>
<imprint>
<date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass>
<keywords scheme="KwdEn" xml:lang="en">
<term>Animals</term>
<term>Calcium Signaling</term>
<term>Cardiomyopathy, Dilated (enzymology)</term>
<term>Cardiomyopathy, Dilated (genetics)</term>
<term>Cardiomyopathy, Dilated (pathology)</term>
<term>Cardiomyopathy, Dilated (prevention & control)</term>
<term>Drosophila Proteins (deficiency)</term>
<term>Drosophila Proteins (genetics)</term>
<term>Drosophila Proteins (metabolism)</term>
<term>Drosophila melanogaster (enzymology)</term>
<term>Drosophila melanogaster (genetics)</term>
<term>Gene Expression Profiling</term>
<term>Genotype</term>
<term>Heart Failure (enzymology)</term>
<term>Heart Failure (genetics)</term>
<term>Heart Failure (pathology)</term>
<term>Membrane Proteins (metabolism)</term>
<term>Mitochondria, Heart (enzymology)</term>
<term>Mitochondria, Heart (pathology)</term>
<term>Mitochondrial Degradation</term>
<term>Mitochondrial Dynamics</term>
<term>Mutation</term>
<term>Myocytes, Cardiac (enzymology)</term>
<term>Myocytes, Cardiac (pathology)</term>
<term>Phenotype</term>
<term>RNA Interference</term>
<term>Reactive Oxygen Species (metabolism)</term>
<term>Signal Transduction</term>
<term>Time Factors</term>
<term>Ubiquitin-Protein Ligases (deficiency)</term>
<term>Ubiquitin-Protein Ligases (genetics)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en">
<term>Drosophila Proteins</term>
<term>Ubiquitin-Protein Ligases</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en">
<term>Cardiomyopathy, Dilated</term>
<term>Drosophila melanogaster</term>
<term>Heart Failure</term>
<term>Mitochondria, Heart</term>
<term>Myocytes, Cardiac</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Cardiomyopathy, Dilated</term>
<term>Drosophila Proteins</term>
<term>Drosophila melanogaster</term>
<term>Heart Failure</term>
<term>Ubiquitin-Protein Ligases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Drosophila Proteins</term>
<term>Membrane Proteins</term>
<term>Reactive Oxygen Species</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Cardiomyopathy, Dilated</term>
<term>Heart Failure</term>
<term>Mitochondria, Heart</term>
<term>Myocytes, Cardiac</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en">
<term>Cardiomyopathy, Dilated</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Calcium Signaling</term>
<term>Gene Expression Profiling</term>
<term>Genotype</term>
<term>Mitochondrial Degradation</term>
<term>Mitochondrial Dynamics</term>
<term>Mutation</term>
<term>Phenotype</term>
<term>RNA Interference</term>
<term>Signal Transduction</term>
<term>Time Factors</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<sec id="S1">
<title>Rationale</title>
<p id="P1">Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood.</p>
</sec>
<sec id="S2">
<title>Objective</title>
<p id="P2">We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in
<italic>Drosophila</italic>
heart tubes.</p>
</sec>
<sec id="S3">
<title>Methods and Results</title>
<p id="P3">Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because
<italic>Drosophila</italic>
lack most of these redundant genes, we examined heart tubes of
<italic>parkin</italic>
knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy.</p>
</sec>
<sec id="S4">
<title>Conclusions</title>
<p id="P4">Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by inhibiting organelle fusion shows promise for minimizing organ dysfunction produced by defective mitophagic signaling.</p>
</sec>
</div>
</front>
</TEI>
<affiliations>
<list></list>
<tree>
<noCountry>
<name sortKey="Bhandari, Poonam" sort="Bhandari, Poonam" uniqKey="Bhandari P" first="Poonam" last="Bhandari">Poonam Bhandari</name>
<name sortKey="Burelle, Yan" sort="Burelle, Yan" uniqKey="Burelle Y" first="Yan" last="Burelle">Yan Burelle</name>
<name sortKey="Chen, Yun" sort="Chen, Yun" uniqKey="Chen Y" first="Yun" last="Chen">Yun Chen</name>
<name sortKey="Dorn, Gerald W" sort="Dorn, Gerald W" uniqKey="Dorn G" first="Gerald W." last="Dorn">Gerald W. Dorn</name>
<name sortKey="Song, Moshi" sort="Song, Moshi" uniqKey="Song M" first="Moshi" last="Song">Moshi Song</name>
</noCountry>
</tree>
</affiliations>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000D31 | SxmlIndent | more

Ou

HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000D31 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Wicri/Canada
   |area=    ParkinsonCanadaV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     PMC:4392818
   |texte=   Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i   -Sk "pubmed:24192653" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd   \
       | NlmPubMed2Wicri -a ParkinsonCanadaV1 

Wicri

This area was generated with Dilib version V0.6.29.
Data generation: Thu May 4 22:20:19 2017. Site generation: Fri Dec 23 23:17:26 2022