| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 100 === 英文摘要
Squamocin is one of acetogenins extracted from Annonaceae plants. Current studies found that squamocin inhibits mitochondrial complex I activity to cause apoptosis and is thought as a new toxin for Parkinson's disease (PD). Understanding the mechanism of action of these toxins in the past has clarified some important causes of Parkinson's disease, and even developed important methods of treatment.
To investigate the mechanism of action of new toxins can provide more information for the mechanism of pathogenesis and new therapies of PD. We previously had shown that squamocin results in apoptosis- (fission) and autophagy-related mitochondrial morphological changes (mitophagy). But the mechanism how squamocin causes different mitochondrial morphological changes and whether apoptosis is correlated with changes in mitochondrial morphology are still unclear.
Cell imaging is applied firstly to investigation whether squamocin-induced changes of mitochondriaand nucleus are correlated. Mitochondrial morphology and nuclear area of microscopic images, respectively, were acquired and quantified by Micro-P and MacBiophotonics Image J.
Squamocin results in decrease, straight tubules and increase of swollen globular mitochondria. After morphological changes in mitochondria, chromatin starts condensing, and the degree of chromatin condensation was correlated with the number of swollen mitochondria. Interestingly, large swollen mitochondrial globules and chromatin condensation occurred faster than cells without starvation. This further confirms that there is strong correlation of formation of large swollen mitochondrial globules with chromatin condensation.
Because squamocin and CCCP reduce mitochondrial membrane potential, effects of squamocin on mitochondrial morphology would be mediated by reduction of mitochondrial membrane potential. Surprisingly, CCCP cannot induce both swollen mitochondrial globules and chromatin condensation. Comparing with CCCP, squamocin induces slow mitochondrial degradation and reduction of mitochondrial membrane potential, and this indicates that such slower reduction of mitochondrial potential may slow down Parkin recruited to mitochondria and further slow down mitophagy to result in more swollen mitochondrial globules. Our results prove this possibility, because squamocin has slowed down association of Parkin with dysfunctional mitochondria, and accumulated of Parkin-associated large swollen mitochondrial globules. Moreover, CCCP can reduce squamocin-induced large swollen mitochondrial globules and chromatin condensation to further confirm this.
According to the results of the above, this is the first finding to demonstrate that a new complex I inhibitor, squamocin, is also an inhibitor to slow down mitophagy. The effects of this new toxin may be mediated by a slow decline in mitochondrial membrane potential to result in that, Parkin could not successfully associate with dysfunctional mitochondria to complete degradation of mitochondria. Then, it results in more swollen dysfunctional mitochondria globules. Such dysfunctional mitochondria may continue producing oxidative stress to leads apoptosis.
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