PrP (122-139) is a covert mitochondrial targeting signal of prion protein and it specifically triggers the perinuclear clustering of mitochondria in neuronal culture cells
| Autor: | Naomi S. Hachiya, Takuto Shimizu, Mayumi Kusano, Yoshimichi Kozuka, Tadashi Yamashita, Masaki Nagane |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
animal diseases Biophysics Mitochondrion Biochemistry Prion Proteins Cell Line Prion Diseases Cell membrane 03 medical and health sciences Mice 0302 clinical medicine Chlorocebus aethiops medicine Animals Humans Molecular Biology Peptide sequence Neurons Chemistry Neurodegeneration Colocalization Cell Biology medicine.disease nervous system diseases Cell biology Mitochondria 030104 developmental biology medicine.anatomical_structure Secretory protein 030220 oncology & carcinogenesis COS Cells Bacterial outer membrane Cristae formation HeLa Cells |
| Zdroj: | Biochemical and biophysical research communications. 524(2) |
| ISSN: | 1090-2104 |
| Popis: | In many neurodegenerative diseases, mitochondria are actively involved in the onset and/or progression of diseases because the energy depletion of the neuronal cells directly leads to the dysfunction and degeneration of cells. In the case of prion diseases, mitochondrial involvement has been reported recently and evidence that prion protein (PrP) is localized in mitochondria is increasing. Despite these findings, the precise molecular mechanism by which PrP targets mitochondria remains unclear. PrP is a secretory protein and does not have a pre-sequence that targets the mitochondria, therefore, we thought that there was a covert signal in the amino acid sequence of PrP. To find the sequence, we constructed various GFP-fused PrP-truncations and colocalization with mitochondria was verified by live-cell imaging. Consequently, we found that 18 amino acids, PrP (122–139), are indispensable for the mitochondrial targeting of PrP. In addition, fluorescent microscopy observation revealed that PrP-localized mitochondria were accumulated at the perinuclear region in neuronal cells such as mouse neuroblastoma Neuro2a (N2a) and prion persistent infection N2a strain (ScN2a), anterograde movement of the mitochondria toward the cell membrane was completely inhibited because of the stacking of PrP on the outer membrane. The cristae formation of perinuclear accumulated mitochondria was disappeared indicating the reduced mitochondrial activity. Surprisingly, PrP-dependent mitochondrial perinuclear accumulation was specifically occurred on neuronal cells, whereas in epithelial HeLa cells and fibroblast COS-7 cells, no perinuclear accumulation observed even after the mitochondrial targeting of PrP. |
| Databáze: | OpenAIRE |
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