Number of the records: 1

Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei

SYSNO ASEP	0461180
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei
Author(s)	Alkhaldi, A.A.M. (GB) Martínek, Jan (BC-A) Panicucci, Brian (BC-A) Dardonville, C. (ES) Zíková, Alena (BC-A)_{RID, ORCID} de Koning, H.P. (GB)
Source Title	International Journal for Parasitology-Drugs and Drug Resistance . - : Elsevier - ISSN 2211-3207 Roč. 6, č. 1 (2016), s. 23-34
Number of pages	12 s.
Publication form	Print - P
Language	eng - English
Country	GB - United Kingdom
Keywords	Trypanosoma brucei ; mitochondrion ; FoF1 ATPase ; succinate dehydrogenase ; phosphonium salt ; SDH complex
Subject RIV	EB - Genetics ; Molecular Biology
R&D Projects	LL1205 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	BC-A - RVO:60077344
UT WOS	000372717200003
EID SCOPUS	84953438596
DOI	10.1016/j.ijpddr.2015.12.002
Annotation	Lipophilic bisphosphonium salts are among the most promising antiprotozoal leads currently under investigation. As part of their preclinical evaluation we here report on their mode of action against African trypanosomes, the etiological agents of sleeping sickness. The bisphosphonium compounds CD38 and AHI-9 exhibited rapid inhibition of Trypanosoma brucei growth, apparently the result of cell cycle arrest that blocked the replication of mitochondrial DNA, contained in the kinetoplast, thereby preventing the initiation of S-phase. Incubation with either compound led to a rapid reduction in mitochondrial membrane potential, and ATP levels decreased by approximately 50% within 1 h. Between 4 and 8 h, cellular calcium levels increased, consistent with release from the depolarized mitochondria. Within the mitochondria, the Succinate Dehydrogenase complex (SDH) was investigated as a target for bisphosphonium salts, but while its subunit 1 (SDH1) was present at low levels in the bloodstream form trypanosomes, the assembled complex was hardly detectable. RNAi knockdown of the SDH1 subunit produced no growth phenotype, either in bloodstream or in the procyclic (insect) forms and we conclude that in trypanosomes SDH is not the target for bisphosphonium salts. Instead, the compounds inhibited ATP production in intact mitochondria, as well as the purified F-1 ATPase, to a level that was similar to 1 mM azide. Co-incubation with azide and bisphosphonium compounds did not inhibit ATPase activity more than either product alone. The results show that, in T. brucei, bisphosphonium compounds do not principally act on succinate dehydrogenase but on the mitochondrial FoF1 ATPase.
Workplace	Biology Centre (since 2006)
Contact	Dana Hypšová, eje@eje.cz, Tel.: 387 775 214
Year of Publishing	2017

Number of the records: 1