MITOL promotes cell survival by degrading Parkin during mitophagy.

Affiliation

Shiiba I(1)(2), Takeda K(2), Nagashima S(2), Ito N(1)(2), Tokuyama T(2), Yamashita SI(3), Kanki T(3), Komatsu T(4), Urano Y(4)(5)(6), Fujikawa Y(7), Inatome R(1)(2), Yanagi S(1)(2).
Author information:
(1)Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Tokyo, Japan.
(2)Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
(3)Department of Cellular Physiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
(4)Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
(5)Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
(6)Core Research for Evolutional Science and Technology
(CREST) Investigator, Japan Agency for Medical Research and Development
(AMED), Tokyo, Japan.
(7)Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.

Abstract

Parkin promotes cell survival by removing damaged mitochondria via mitophagy. However, although some studies have suggested that Parkin induces cell death, the regulatory mechanism underlying the dual role of Parkin remains unknown. Herein, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) regulates Parkin-mediated cell death through the FKBP38-dependent dynamic translocation from the mitochondria to the ER during mitophagy. Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine-tunes mitophagy by controlling the quantity of Parkin. Deletion of MITOL leads to accumulation of the phosphorylated active form of Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. Thus, we have shown that MITOL blocks Parkin-induced cell death, at least partially, by protecting FKBP38 from Parkin. Our findings unveil the regulation of the dual function of Parkin and provide a novel perspective on the pathogenesis of PD.