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Publication

PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions.

Molecular cell | 2018

Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic remodeling among distinct subcellular regions and the Parkinson's disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria increase crista junctions and numbers in selective subcellular areas, and this remodeling requires PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60/mitofilin, which stabilizes MIC60 oligomerization. Expression of MIC60 restores crista structure and ATP levels of PINK1-null flies and remarkably rescues their behavioral defects and dopaminergic neurodegeneration. In an extension to human relevance, we discover that the PINK1-MIC60 pathway is conserved in human neurons, and expression of several MIC60 coding variants in the mitochondrial targeting sequence found in PD patients in Drosophila impairs crista junction formation and causes locomotion deficits. These findings highlight the importance of maintenance and plasticity of crista junctions to cellular homeostasis in vivo.

Pubmed ID: 29456190 RIS Download

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Associated grants

Agency: NCRR NIH HHS, United States
Id: S10 RR026780
Agency: NINDS NIH HHS, United States
Id: R01 NS078086
Agency: NINDS NIH HHS, United States
Id: P50 NS072187

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Collection of data of protein sequence and functional information. Resource for protein sequence and annotation data. Consortium for preservation of the UniProt databases: UniProt Knowledgebase (UniProtKB), UniProt Reference Clusters (UniRef), and UniProt Archive (UniParc), UniProt Proteomes. Collaboration between European Bioinformatics Institute (EMBL-EBI), SIB Swiss Institute of Bioinformatics and Protein Information Resource. Swiss-Prot is a curated subset of UniProtKB.

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Parkinson's Progression Markers Initiative (tool)

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An observational longitudinal clinical study partnership to identify and validate biomarkers of Parkinson disease (PD) progression and provide easy and open web-based access to the comprehensive set of correlated clinical data and biospecimens, information, and biosamples acquired from PD and age and gender matched healthy control subjects to the research community. The data and specimens have been collected in a standardized manner under strict protocols and includes clinical (demographic, motor and non-motor, cognitive and neurobehavioral), imaging (raw and processed MRI, SPECT and DAT), and blood chemistry and hematology subject assessments and biospecimen inventories (serum, plasma, whole blood, CSF, DNA, RNA and urine). All data are de-identified to protect patient privacy. PPMI will be carried out over five years at 21 clinical sites in the United States and Europe and requires the participation of 400 Parkinson's patients and 200 control participants. The PPMI database provides researchers with access to correlated clinical and imaging data, along with annotated biospecimens, all available within an open access system that encourages data sharing (http://www.ppmi-info.org/access-data-specimens/). The website hosts an Ongoing Analysis section to keep the scientific community apprised of analyses being completed, in hopes of stimulating collaborations between researchers who are using PPMI data and specimens.

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Database that aggregates exome and genome sequencing data from large-scale sequencing projects. The gnomAD data set contains individuals sequenced using multiple exome capture methods and sequencing chemistries. Raw data from the projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects.

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