PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions
Journal
Molecular Cell
Journal Volume
69
Journal Issue
5
Pages
744-756 e.6
Date Issued
2018
Author(s)
Tsai P.-I.
Hsieh C.-H.
Papakyrikos A.M.
Kim M.J.
Napolioni V.
Schoor C.
Couthouis J.
Wszolek Z.K.
Winter D.
Greicius M.D.
Ross O.A.
Wang X.
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. Tsai et al. discover that mitochondria increase crista junctions and numbers in selective subcellular areas in Drosophila. This structural remodeling requires Parkinson's-linked PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60, which stabilizes MIC60 oligomerization. MIC60 functions downstream of PINK1 to maintain mitochondrial functions and cellular survival. ? 2018 Elsevier Inc.
SDGs
Other Subjects
mitochondrial protein; mitofilin; PINK1 protein; protein serine threonine kinase; unclassified drug; Drosophila protein; IMMT protein, human; mitochondrial protein; muscle protein; PINK1 protein, Drosophila; protein kinase; protein serine threonine kinase; PTEN-induced putative kinase; adult; animal cell; Article; axon; cell density; cell organelle; cell plasticity; controlled study; Drosophila; HEK293T cell line; homeostasis; human; human cell; locomotion; mitochondrial membrane; mitochondrial targeting signal; mitochondrial volume; mitochondrion; nerve cell; nerve degeneration; nonhuman; oligomerization; phenotype; protein expression; protein phosphorylation; steady state; transmission electron microscopy; upregulation; animal; Drosophila melanogaster; genetics; metabolism; Parkinson disease; pathology; phosphorylation; Animals; Drosophila melanogaster; Drosophila Proteins; Humans; Mitochondrial Membranes; Mitochondrial Proteins; Muscle Proteins; Neurons; Parkinson Disease; Phosphorylation; Protein Kinases; Protein-Serine-Threonine Kinases
Type
journal article