Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance
- Zhihao Wu1,
- Tomoyo Sawada2,3,
- Kahori Shiba4,
- Song Liu1,
- Tomoko Kanao5,
- Ryosuke Takahashi2,3,
- Nobutaka Hattori4,5,6,
- Yuzuru Imai6,7 and
- Bingwei Lu1,7
- 1Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
- 2Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
- 3CREST (Core Research for Evolutionary Science and Technology), Japan Science and Technology Agency, Saitama 332-0012, Japan;
- 4Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
- 5Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
- 6Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Abstract
Eukaryotes employ elaborate mitochondrial quality control (MQC) to maintain the function of the power-generating organelle. Parkinson's disease-associated PINK1 and Parkin actively participate in MQC. However, the signaling events involved are largely unknown. Here we show that mechanistic target of rapamycin 2 (mTORC2) and Tricornered (Trc) kinases act downstream from PINK1 to regulate MQC. Trc is phosphorylated in mTORC2-dependent and mTORC2-independent manners and is specifically localized to mitochondria in response to PINK1, which regulates mTORC2 through mitochondrial complex-I activity. Genetically, mTORC2 and Trc act upstream of Parkin. Thus, multiplex kinase signaling is acting between PINK1 and Parkin to regulate MQC, a process highly conserved in mammals.
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Footnotes
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↵7 Corresponding authors
E-mail bingwei{at}stanford.edu
E-mail yzimai{at}juntendo.ac.jp
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.203406.112.
- Received August 13, 2012.
- Accepted December 4, 2012.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press
