Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin
| Autor: | Matthew J. LaVoie, Jonathan D. Nardozzi, Bethann N. Johnson, Rakshita A. Charan, S Zaganelli |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Programmed cell death Ubiquitin-Protein Ligases Immunology Population Amino Acid Motifs Down-Regulation Apoptosis Biology Mitochondrion Parkin 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Bcl-2-associated X protein Ubiquitin Mitophagy Humans education Cells Cultured 030304 developmental biology bcl-2-Associated X Protein Neurons 0303 health sciences education.field_of_study Parkinson Disease Cell Biology Cell biology Ubiquitin ligase nervous system diseases Mitochondria Protein Transport biology.protein Original Article 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, affecting 1–3% of the population over 65. Mutations in the ubiquitin E3 ligase parkin are the most common cause of autosomal recessive PD. The parkin protein possesses potent cell-protective properties and has been mechanistically linked to both the regulation of apoptosis and the turnover of damaged mitochondria. Here, we explored these two functions of parkin and the relative scale of these processes in various cell types. While biochemical analyses and subcellular fractionation were sufficient to observe robust parkin-dependent mitophagy in immortalized cells, higher resolution techniques appear to be required for primary culture systems. These approaches, however, did affirm a critical role for parkin in the regulation of apoptosis in primary cultured neurons and all other cells studied. Our prior work demonstrated that parkin-dependent ubiquitination of endogenous Bax inhibits its mitochondrial translocation and can account for the anti-apoptotic effects of parkin. Having found a central role for parkin in the regulation of apoptosis, we further investigated the parkin-Bax interaction. We observed that the BH3 domain of Bax is critical for its recognition by parkin, and identified two lysines that are crucial for parkin-dependent regulation of Bax translocation. Last, a disease-linked mutation in parkin failed to influence Bax translocation to mitochondria after apoptotic stress. Taken together, our data suggest that regulation of apoptosis by the inhibition of Bax translocation is a prevalent physiological function of parkin regardless of the kind of cell stress, preventing overt cell death and supporting cell viability during mitochondrial injury and repair. |
| Databáze: | OpenAIRE |
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