PKA Regulates PINK1 Stability and Parkin Recruitment to Damaged Mitochondria through Phosphorylation of MIC60

Shiori Akabane, Midori Uno, Naoki Tani, Shunta Shimazaki, Natsumi Ebara, Hiroki Kato, Hidetaka Kosako, Toshihiko Oka

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

A mitochondrial kinase, PTEN-induced putative kinase 1 (PINK1), selectively recruits the ubiquitin ligase Parkin to damaged mitochondria, which modifies mitochondria by polyubiquitination, leading to mitochondrial autophagy. Here, we report that treatment with an adenylate cyclase agonist or expression of protein kinase A (PKA) impairs Parkin recruitment to damaged mitochondria and decreases PINK1 protein levels. We identified a mitochondrial membrane protein, MIC60 (also known as mitofilin), as a PKA substrate. Mutational and mass spectrometric analyses revealed that the Ser528 residue of MIC60 undergoes PKA-dependent phosphorylation. MIC60 transiently interacts with PINK1, and MIC60 downregulation leads to a reduction in PINK1 and mislocalization of Parkin. Phosphorylation-mimic mutants of MIC60 fail to restore the defect in Parkin recruitment in MIC60-knocked down cells, whereas a phosphorylation-deficient MIC60 mutant facilitates the mitochondrial localization of Parkin. Our findings indicate that PKA-mediated phosphorylation of MIC60 negatively regulates mitochondrial clearance that is initiated by PINK1 and Parkin.

Original languageEnglish
Pages (from-to)371-384
Number of pages14
JournalMolecular Cell
Volume62
Issue number3
DOIs
Publication statusPublished - May 5 2016

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Cyclic AMP-Dependent Protein Kinases
Mitochondria
Phosphorylation
Mitochondrial Proteins
Autophagy
Mitochondrial Membranes
Ligases
Ubiquitin
Adenylyl Cyclases
Membrane Proteins
Phosphotransferases
Down-Regulation
PTEN-induced putative kinase
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

PKA Regulates PINK1 Stability and Parkin Recruitment to Damaged Mitochondria through Phosphorylation of MIC60. / Akabane, Shiori; Uno, Midori; Tani, Naoki; Shimazaki, Shunta; Ebara, Natsumi; Kato, Hiroki; Kosako, Hidetaka; Oka, Toshihiko.

In: Molecular Cell, Vol. 62, No. 3, 05.05.2016, p. 371-384.

Research output: Contribution to journalArticle

Akabane, Shiori ; Uno, Midori ; Tani, Naoki ; Shimazaki, Shunta ; Ebara, Natsumi ; Kato, Hiroki ; Kosako, Hidetaka ; Oka, Toshihiko. / PKA Regulates PINK1 Stability and Parkin Recruitment to Damaged Mitochondria through Phosphorylation of MIC60. In: Molecular Cell. 2016 ; Vol. 62, No. 3. pp. 371-384.
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