PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis
Shireen A. Sarraf,
Dionisia P. Sideris,
Nikolaos Giagtzoglou,
Lina Ni,
Mark W. Kankel,
Anindya Sen,
Lauren E. Bochicchio,
Chiu-Hui Huang,
Samuel C. Nussenzweig,
Stuart H. Worley,
Paul D. Morton,
Spyros Artavanis-Tsakonas,
Richard J. Youle,
Alicia M. Pickrell
Affiliations
Shireen A. Sarraf
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Dionisia P. Sideris
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Nikolaos Giagtzoglou
Pathway Discovery Laboratory, Biogen, Inc., Cambridge, MA 02142, USA
Lina Ni
School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Mark W. Kankel
Neuromuscular & Movement Disorders, Biogen, Inc., Cambridge, MA 02142, USA
Anindya Sen
Pathway Discovery Laboratory, Biogen, Inc., Cambridge, MA 02142, USA
Lauren E. Bochicchio
Translational Biology, Medicine, and Health Graduate Program, Virginia Polytechnic Institute and State University, Roanoke, VA 24016, USA
Chiu-Hui Huang
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Samuel C. Nussenzweig
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Stuart H. Worley
School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Paul D. Morton
Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
Spyros Artavanis-Tsakonas
Pathway Discovery Laboratory, Biogen, Inc., Cambridge, MA 02142, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Richard J. Youle
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Alicia M. Pickrell
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA; Corresponding author
Summary: PINK1 and Parkin are established mediators of mitophagy, the selective removal of damaged mitochondria by autophagy. PINK1 and Parkin have been proposed to act as tumor suppressors, as loss-of-function mutations are correlated with enhanced tumorigenesis. However, it is unclear how PINK1 and Parkin act in coordination during mitophagy to influence the cell cycle. Here we show that PINK1 and Parkin genetically interact with proteins involved in cell cycle regulation, and loss of PINK1 and Parkin accelerates cell growth. PINK1- and Parkin-mediated activation of TBK1 at the mitochondria during mitophagy leads to a block in mitosis due to the sequestration of TBK1 from its physiological role at centrosomes during mitosis. Our study supports a diverse role for the far-reaching, regulatory effects of mitochondrial quality control in cellular homeostasis and demonstrates that the PINK1/Parkin pathway genetically interacts with the cell cycle, providing a framework for understanding the molecular basis linking PINK1 and Parkin to mitosis. : Sarraf et al. use mouse and fly genetics to discover that PINK1 and Parkin influence cell cycle progression. Mitophagy and mitosis independently activate TBK1 at damaged mitochondria and centrosomes, respectively, influencing whether the cell will address mitochondrial quality control or progress with proliferation. Keywords: PINK1, Parkin, mitosis, mitophagy, TBK1, cell cycle, ATM, centrosome, tank binding kinase 1, ik2
