2. Academic Validation
  3. PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions

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

  • Mol Cell. 2018 Mar 1;69(5):744-756.e6. doi: 10.1016/j.molcel.2018.01.026.
Pei-I Tsai 1,  Chin-Hsien Lin 2,  Chung-Han Hsieh 1,  Amanda M Papakyrikos 3,  Min Joo Kim 1,  Valerio Napolioni 4,  Carmen Schoor 5,  Julien Couthouis 6,  Ruey-Meei Wu 2,  Zbigniew K Wszolek 7,  Dominic Winter 5,  Michael D Greicius 4,  Owen A Ross 8,  Xinnan Wang 9
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2 Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan.
  • 3 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Graduate Program in Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 4 Functional Imaging in Neuropsychiatric Disorders (FIND) Lab, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 5 Institute for Biochemistry and Molecular Biology, University of Bonn, Bonn 53115, Germany.
  • 6 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 7 Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
  • 8 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • 9 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 29456190 DOI: 10.1016/j.molcel.2018.01.026
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.

Keywords

Drosophila; MIC60; PINK1; Parkinson’s; cristae; mitochondria; mitofilin; oligomerization; phosphorylation; variant.

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