Unexpected mitochondrial matrix localization of Parkinson's disease‐related DJ‐1 mutants but not wild‐type DJ‐1 |
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| Authors: | Waka Kojima Yuki Kujuro Kei Okatsu Queliconi Bruno Fumika Koyano Mayumi Kimura Koji Yamano Keiji Tanaka Noriyuki Matsuda |
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| Affiliation: | 1. Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;2. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan;3. Tachikawa Hospital, Tokyo, Japan;4. Department of Neurology, Keio University School of Medicine, Tokyo, Japan;5. Structural Biology Laboratory, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan;6. Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;7. PRESTO, JST, Saitama, Japan |
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| Abstract: | DJ‐1 has been identified as a gene responsible for recessive familial Parkinson's disease (familial Parkinsonism), which is caused by a mutation in the PARK7 locus. Consistent with the inferred correlation between Parkinson's disease and mitochondrial impairment, mitochondrial localization of DJ‐1 and its implied role in mitochondrial quality control have been reported. However, the mechanism by which DJ‐1 affects mitochondrial function remains poorly defined, and the mitochondrial localization of DJ‐1 is still controversial. Here, we show the mitochondrial matrix localization of various pathogenic and artificial DJ‐1 mutants by multiple independent experimental approaches including cellular fractionation, proteinase K protection assays, and specific immunocytochemistry. Localization of various DJ‐1 mutants to the matrix is dependent on the membrane potential and translocase activity in both the outer and the inner membranes. Nevertheless, DJ‐1 possesses neither an amino‐terminal alpha‐helix nor a predictable matrix‐targeting signal, and a post‐translocation processing‐derived molecular weight change is not observed. In fact, wild‐type DJ‐1 does not show any evidence of mitochondrial localization at all. Such a mode of matrix localization of DJ‐1 is difficult to explain by conventional mechanisms and implies a unique matrix import mechanism for DJ‐1 mutants. |
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