Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin
Identifieur interne : 001606 ( Ncbi/Checkpoint ); précédent : 001605; suivant : 001607Mitochondrial 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. DornSource :
- Circulation research [ 0009-7330 ] ; 2013.
English descriptors
- KwdEn :
- Animals, Calcium Signaling, Cardiomyopathy, Dilated (enzymology), Cardiomyopathy, Dilated (genetics), Cardiomyopathy, Dilated (pathology), Cardiomyopathy, Dilated (prevention & control), Drosophila Proteins (deficiency), Drosophila Proteins (genetics), Drosophila Proteins (metabolism), Drosophila melanogaster (enzymology), Drosophila melanogaster (genetics), Gene Expression Profiling, Genotype, Heart Failure (enzymology), Heart Failure (genetics), Heart Failure (pathology), Membrane Proteins (metabolism), Mitochondria, Heart (enzymology), Mitochondria, Heart (pathology), Mitochondrial Degradation, Mitochondrial Dynamics, Mutation, Myocytes, Cardiac (enzymology), Myocytes, Cardiac (pathology), Phenotype, RNA Interference, Reactive Oxygen Species (metabolism), Signal Transduction, Time Factors, Ubiquitin-Protein Ligases (deficiency), Ubiquitin-Protein Ligases (genetics).
- MESH :
- chemical , deficiency : Drosophila Proteins, Ubiquitin-Protein Ligases.
- enzymology : Cardiomyopathy, Dilated, Drosophila melanogaster, Heart Failure, Mitochondria, Heart, Myocytes, Cardiac.
- genetics : Cardiomyopathy, Dilated, Drosophila Proteins, Drosophila melanogaster, Heart Failure, Ubiquitin-Protein Ligases.
- chemical , metabolism : Drosophila Proteins, Membrane Proteins, Reactive Oxygen Species.
- pathology : Cardiomyopathy, Dilated, Heart Failure, Mitochondria, Heart, Myocytes, Cardiac.
- prevention & control : Cardiomyopathy, Dilated.
- Animals, Calcium Signaling, Gene Expression Profiling, Genotype, Mitochondrial Degradation, Mitochondrial Dynamics, Mutation, Phenotype, RNA Interference, Signal Transduction, Time Factors.
Abstract
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.
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
Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because
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:
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PMC:4392818Le document en format XML
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Hearts and Its Containment by Suppressing Mitofusin</title>
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<author><name sortKey="Song, Moshi" sort="Song, Moshi" uniqKey="Song M" first="Moshi" last="Song">Moshi Song</name>
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<author><name sortKey="Chen, Yun" sort="Chen, Yun" uniqKey="Chen Y" first="Yun" last="Chen">Yun Chen</name>
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<author><name sortKey="Burelle, Yan" sort="Burelle, Yan" uniqKey="Burelle Y" first="Yan" last="Burelle">Yan Burelle</name>
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<author><name sortKey="Dorn, Gerald W" sort="Dorn, Gerald W" uniqKey="Dorn G" first="Gerald W." last="Dorn">Gerald W. Dorn</name>
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<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>
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<author><name sortKey="Chen, Yun" sort="Chen, Yun" uniqKey="Chen Y" first="Yun" last="Chen">Yun Chen</name>
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<series><title level="j">Circulation research</title>
<idno type="ISSN">0009-7330</idno>
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<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>
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<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>
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<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>
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