PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria

Kei Okatsu, Toshihiko Oka, Masahiro Iguchi, Kenji Imamura, Hidetaka Kosako, Naoki Tani, Mayumi Kimura, Etsu Go, Fumika Koyano, Manabu Funayama, Kahori Shiba-Fukushima, Shigeto Sato, Hideaki Shimizu, Yuko Fukunaga, Hisaaki Taniguchi, Masaaki Komatsu, Nobutaka Hattori, Katsuyoshi Mihara, Keiji Tanaka and Noriyuki Matsuda ()
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Kei Okatsu: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Toshihiko Oka: College of Science, Rikkyo University, Toshimaku-ku
Masahiro Iguchi: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Kenji Imamura: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Hidetaka Kosako: Institute for Enzyme Research, The University of Tokushima
Naoki Tani: Institute for Enzyme Research, The University of Tokushima
Mayumi Kimura: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Etsu Go: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Fumika Koyano: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Manabu Funayama: Juntendo University School of Medicine
Kahori Shiba-Fukushima: Juntendo University School of Medicine
Shigeto Sato: Juntendo University School of Medicine
Hideaki Shimizu: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho
Yuko Fukunaga: Graduate School of Medical Science, Kyushu University
Hisaaki Taniguchi: Institute for Enzyme Research, The University of Tokushima
Masaaki Komatsu: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science
Nobutaka Hattori: Juntendo University School of Medicine
Katsuyoshi Mihara: Graduate School of Medical Science, Kyushu University
Keiji Tanaka: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Noriyuki Matsuda: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science

Nature Communications, 2012, vol. 3, issue 1, 1-10

Abstract: Abstract Dysfunction of PINK1, a mitochondrial Ser/Thr kinase, causes familial Parkinson's disease (PD). Recent studies have revealed that PINK1 is rapidly degraded in healthy mitochondria but accumulates on the membrane potential (ΔΨm)-deficient mitochondria, where it recruits another familial PD gene product, Parkin, to ubiquitylate the damaged mitochondria. Despite extensive study, the mechanism underlying the homeostatic control of PINK1 remains unknown. Here we report that PINK1 is autophosphorylated following a decrease in ΔΨm and that most disease-relevant mutations hinder this event. Mass spectrometric and mutational analyses demonstrate that PINK1 autophosphorylation occurs at Ser228 and Ser402, residues that are structurally clustered together. Importantly, Ala mutation of these sites abolishes autophosphorylation of PINK1 and inhibits Parkin recruitment onto depolarized mitochondria, whereas Asp (phosphorylation-mimic) mutation promotes mitochondrial localization of Parkin even though autophosphorylation was still compromised. We propose that autophosphorylation of Ser228 and Ser402 in PINK1 is essential for efficient mitochondrial localization of Parkin.

Date: 2012
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DOI: 10.1038/ncomms2016

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