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PMID:29456190

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Citation

Tsai, PI, Lin, CH, Hsieh, CH, Papakyrikos, AM, Kim, MJ, Napolioni, V, Schoor, C, Couthouis, J, Wu, RM, Wszolek, ZK, Winter, D, Greicius, MD, Ross, OA and Wang, X (2018) PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions. Mol. Cell 69:744-756.e6

Abstract

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.

Links

PubMed Online version:10.1016/j.molcel.2018.01.026

Keywords

Animals; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster; Humans; Mitochondrial Membranes/metabolism; Mitochondrial Membranes/pathology; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism; Muscle Proteins/genetics; Muscle Proteins/metabolism; Neurons/metabolism; Neurons/pathology; Parkinson Disease/genetics; Parkinson Disease/metabolism; Parkinson Disease/pathology; Phosphorylation/genetics; Protein Kinases/genetics; Protein Kinases/metabolism; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:MIC60

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0029891

F

Seeded From UniProt

complete

DROME:MIC60

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:MIC60

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:MIC60

enables

GO:0043008: ATP-dependent protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0029891

F

Seeded From UniProt

complete

DROME:MIC60

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:PINK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0019960

F

Seeded From UniProt

complete

DROME:PINK1

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:PINK1

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:PINK1

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:PINK1

enables

GO:0043008: ATP-dependent protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0019960

F

Seeded From UniProt

complete

DROME:PINK1

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:PRKN

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q0KHV6

part_of

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q0KHV6

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q0KHV6

enables

GO:0043008: ATP-dependent protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0019960

F

Seeded From UniProt

complete

DROME:Q0KHV6

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q0KHV6

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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