Ha Young Ran, Hwang Bae-Geun, Hong Yeonchul, Yang Hye-Won, Lee Sang Joon
Division of Integrative Bioscience and Bioengineering, Center for Biofluid and Biomimic Research, Pohang University of Science and Technology, Pohang 790-784, Korea.
Department of Mechanical Engineering, Center for Biofluid and Biomimic Research, Pohang University of Science and Technology, Pohang 790-784, Korea.
Korean J Parasitol. 2015 Aug;53(4):421-30. doi: 10.3347/kjp.2015.53.4.421. Epub 2015 Aug 25.
The parasite Plasmodium falciparum causes severe malaria and is the most dangerous to humans. However, it exhibits resistance to their drugs. Farnesyltransferase has been identified in pathogenic protozoa of the genera Plasmodium and the target of farnesyltransferase includes Ras family. Therefore, the inhibition of farnesyltransferase has been suggested as a new strategy for the treatment of malaria. However, the exact functional mechanism of this agent is still unknown. In addition, the effect of farnesyltransferase inhibitor (FTIs) on mitochondrial level of malaria parasites is not fully understood. In this study, therefore, the effect of a FTI R115777 on the function of mitochondria of P. falciparum was investigated experimentally. As a result, FTI R115777 was found to suppress the infection rate of malaria parasites under in vitro condition. It also reduces the copy number of mtDNA-encoded cytochrome c oxidase III. In addition, the mitochondrial membrane potential (ΔΨm) and the green fluorescence intensity of MitoTracker were decreased by FTI R115777. Chloroquine and atovaquone were measured by the mtDNA copy number as mitochondrial non-specific or specific inhibitor, respectively. Chloroquine did not affect the copy number of mtDNA-encoded cytochrome c oxidase III, while atovaquone induced to change the mtDNA copy number. These results suggest that FTI R115777 has strong influence on the mitochondrial function of P. falciparum. It may have therapeutic potential for malaria by targeting the mitochondria of parasites.
恶性疟原虫这种寄生虫会引发严重疟疾，对人类危害极大。然而，它对药物产生了抗性。法尼基转移酶已在疟原虫属的致病原生动物中被鉴定出来，且法尼基转移酶的作用靶点包括Ras家族。因此，抑制法尼基转移酶被提议作为治疗疟疾的新策略。然而，这种药物的确切作用机制仍不清楚。此外，法尼基转移酶抑制剂（FTIs）对疟原虫线粒体水平的影响尚未完全明确。因此，在本研究中，通过实验研究了FTI R115777对恶性疟原虫线粒体功能的影响。结果发现，FTI R115777在体外条件下能抑制疟原虫的感染率。它还能减少线粒体DNA编码的细胞色素c氧化酶III的拷贝数。此外，FTI R115777降低了线粒体膜电位（ΔΨm）和MitoTracker的绿色荧光强度。分别以线粒体DNA拷贝数来检测氯喹和阿托伐醌，它们分别作为线粒体非特异性或特异性抑制剂。氯喹不影响线粒体DNA编码的细胞色素c氧化酶III的拷贝数，而阿托伐醌则诱导线粒体DNA拷贝数发生变化。这些结果表明，FTI R115777对恶性疟原虫的线粒体功能有强烈影响。它可能通过靶向寄生虫的线粒体而具有治疗疟疾的潜力。
