Recognizing the cooperative and independent mitochondrial functions of Parkin and PINK1
| Autor: | Bethann N. Johnson, Matthew J. LaVoie, Rakshita A. Charan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Programmed cell death
autophagy Parkinson's disease Cell Survival Ubiquitin-Protein Ligases education PINK1 Mitochondrion Editorials: Cell Cycle Features Parkin 03 medical and health sciences 0302 clinical medicine Bcl-2-associated X protein Ubiquitin medicine Animals Humans Molecular Biology 030304 developmental biology bcl-2-Associated X Protein Genetics 0303 health sciences biology Autophagy digestive oral and skin physiology apoptosis Ubiquitination Parkinson Disease Cell Biology medicine.disease equipment and supplies humanities nervous system diseases Cell biology Mitochondria stomatognathic diseases Bax biology.protein Parkinson’s disease Drosophila Protein Kinases 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Cell Cycle |
| ISSN: | 1551-4005 1538-4101 |
| Popis: | literature predicting a direct downstream function within a highly conserved cell death pathway. Soon after the cloning of the PARKIN gene, numerous studies shed light on the function of parkin. Parallel efforts from many groups also revealed that parkin is dramatically sensitive to stress-induced mis-folding, aggregation and inactivation, with some studies reporting alterations in parkin solubility in diseased human brain tissue. 5 However, it is difficult to reconcile the potent and widely accepted protective effects of parkin with the fact that at the biochemical level parkin is rapidly inactivated or made insoluble during cell stress. In the rational design of a pro-survival protein, many considerations would be made. At the primary sequence level, for example, highly reactive and modification-prone cysteines would be limited or excluded altogether; parkin has 35 cysteine residues. In terms of secondary structure, a stress-tolerant conformation would be desirable but is not found in parkin. The paradox of parkin-induced protection against stress and stressinduced parkin dysfunction inspired us to ask how parkin could promote cell survival in spite of an acute, stress-induced loss of parkin function. Our most recent data provide insight. We propose that a parkin-dependent reduction in mitochondrial Bax and the reduced propensity for apoptosis perpetuate a pro-survival state, even in the absence of parkin itself. Akin to how receptor densities establish longterm changes in the sensitivity of neurons to depolarization, by reducing mitochondrial Bax parkin may establish a “desensitized state” within the intrinsic apoptotic pathway that persists long after parkin has been inactivated by stress. |
| Databáze: | OpenAIRE |
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