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

Pei I. Tsai, Chin Hsien Lin, Chung Han Hsieh, Amanda M. Papakyrikos, Min Joo Kim, Valerio Napolioni, Carmen Schoor, Julien Couthouis, Ruey Meei Wu, Zbigniew K Wszolek, Dominic Winter, Michael D. Greicius, Owen A Ross, Xinnan Wang

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)744-756.e6
JournalMolecular Cell
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2018

Fingerprint

Drosophila
Mitochondrial Proteins
Mitochondrial Membranes
Parkinson Disease
Mitochondria
Membrane Proteins
Locomotion
Diptera
Homeostasis
Phosphotransferases
Adenosine Triphosphate
Maintenance
Neurons
Survival

Keywords

  • cristae
  • Drosophila
  • MIC60
  • mitochondria
  • mitofilin
  • oligomerization
  • Parkinson's
  • phosphorylation
  • PINK1
  • variant

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Tsai, P. I., Lin, C. H., Hsieh, C. H., Papakyrikos, A. M., Kim, M. J., Napolioni, V., ... Wang, X. (2018). PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions. Molecular Cell, 69(5), 744-756.e6. https://doi.org/10.1016/j.molcel.2018.01.026

PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions. / Tsai, Pei I.; Lin, Chin Hsien; Hsieh, Chung Han; Papakyrikos, Amanda M.; Kim, Min Joo; Napolioni, Valerio; Schoor, Carmen; Couthouis, Julien; Wu, Ruey Meei; Wszolek, Zbigniew K; Winter, Dominic; Greicius, Michael D.; Ross, Owen A; Wang, Xinnan.

In: Molecular Cell, Vol. 69, No. 5, 01.03.2018, p. 744-756.e6.

Research output: Contribution to journalArticle

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 & Wang, X 2018, 'PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions', Molecular Cell, vol. 69, no. 5, pp. 744-756.e6. https://doi.org/10.1016/j.molcel.2018.01.026
Tsai, Pei I. ; Lin, Chin Hsien ; Hsieh, Chung Han ; Papakyrikos, Amanda M. ; Kim, Min Joo ; Napolioni, Valerio ; Schoor, Carmen ; Couthouis, Julien ; Wu, Ruey Meei ; Wszolek, Zbigniew K ; Winter, Dominic ; Greicius, Michael D. ; Ross, Owen A ; Wang, Xinnan. / PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions. In: Molecular Cell. 2018 ; Vol. 69, No. 5. pp. 744-756.e6.
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