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J Biol Chem. 2016 Jul 29;291(31):16162-74. doi: 10.1074/jbc.M116.714923. Epub 2016 Jun 14.

Constitutive Activation of PINK1 Protein Leads to Proteasome-mediated and Non-apoptotic Cell Death Independently of Mitochondrial Autophagy.

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From the Department of Life Science, Rikkyo University, -34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501.
the Institute of Nephrology, Department of Cellular Physiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, and.
the Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
From the Department of Life Science, Rikkyo University, -34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501,


Phosphatase and tensin homolog-induced putative kinase 1 (PINK1), a Ser/Thr kinase, and PARKIN, a ubiquitin ligase, are causal genes for autosomal recessive early-onset parkinsonism. Multiple lines of evidence indicate that PINK1 and PARKIN cooperatively control the quality of the mitochondrial population via selective degradation of damaged mitochondria by autophagy. Here, we report that PINK1 and PARKIN induce cell death with a 12-h delay after mitochondrial depolarization, which differs from the time profile of selective autophagy of mitochondria. This type of cell death exhibited definite morphologic features such as plasma membrane rupture, was insensitive to a pan-caspase inhibitor, and did not involve mitochondrial permeability transition. Expression of a constitutively active form of PINK1 caused cell death in the presence of a pan-caspase inhibitor, irrespective of the mitochondrial membrane potential. PINK1-mediated cell death depended on the activities of PARKIN and proteasomes, but it was not affected by disruption of the genes required for autophagy. Furthermore, fluorescence and electron microscopic analyses revealed that mitochondria were still retained in the dead cells, indicating that PINK1-mediated cell death is not caused by mitochondrial loss. Our findings suggest that PINK1 and PARKIN play critical roles in selective cell death in which damaged mitochondria are retained, independent of mitochondrial autophagy.


PTEN-induced putative kinase 1 (PINK1); cell death; mitochondria; mitophagy; parkin

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