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Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.

ABSTRACT: Loss of the E3 ubiquitin ligase Parkin causes early onset Parkinson's disease, a neurodegenerative disorder of unknown etiology. Parkin has been linked to multiple cellular processes including protein degradation, mitochondrial homeostasis, and autophagy; however, its precise role in pathogenesis is unclear. Recent evidence suggests that Parkin is recruited to damaged mitochondria, possibly affecting mitochondrial fission and/or fusion, to mediate their autophagic turnover. The precise mechanism of recruitment and the ubiquitination target are unclear. Here we show in Drosophila cells that PINK1 is required to recruit Parkin to dysfunctional mitochondria and promote their degradation. Furthermore, PINK1 and Parkin mediate the ubiquitination of the profusion factor Mfn on the outer surface of mitochondria. Loss of Drosophila PINK1 or parkin causes an increase in Mfn abundance in vivo and concomitant elongation of mitochondria. These findings provide a molecular mechanism by which the PINK1/Parkin pathway affects mitochondrial fission/fusion as suggested by previous genetic interaction studies. We hypothesize that Mfn ubiquitination may provide a mechanism by which terminally damaged mitochondria are labeled and sequestered for degradation by autophagy.

SUBMITTER: Ziviani E

PROVIDER: S-EPMC2841909 | biostudies-other | 2010 Mar

REPOSITORIES: biostudies-other

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Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.

Ziviani Elena E Tao Ran N RN Whitworth Alexander J AJ

Proceedings of the National Academy of Sciences of the United States of America 20100301 11

Loss of the E3 ubiquitin ligase Parkin causes early onset Parkinson's disease, a neurodegenerative disorder of unknown etiology. Parkin has been linked to multiple cellular processes including protein degradation, mitochondrial homeostasis, and autophagy; however, its precise role in pathogenesis is unclear. Recent evidence suggests that Parkin is recruited to damaged mitochondria, possibly affecting mitochondrial fission and/or fusion, to mediate their autophagic turnover. The precise mechanism ...[more]

PMID: 20194754

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Project description:RationaleDysfunctional 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.ObjectiveWe 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 resultsTranscriptional 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.ConclusionsParkin 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.

Dataset Information

Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.

Publications

Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.

Similar Datasets

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