title: Acriflavine treatment promotes dyskinetoplasty in Trypanosoma cruzi as revealed by ultrastructural analysis.
abstract: Trypanosomatid mitochondrial DNA is structured as a giant network of thousands of interlocked DNA molecules enclosed within the kinetoplast. The structure and replication mechanism of kinetoplast DNA (kDNA) is unique, thereby making it an excellent chemotherapeutic target. Alteration in the structural organization of kDNA can give rise to dyskinetoplastic (Dk) strains. In Dk cells, the kDNA is dispersed in clumps throughout the mitochondrial matrix and not organized into a network. In this work, Trypanosoma cruzi epimastigotes were treated with acriflavine, a DNA intercalating drug, which promoted a decrease in cell proliferation and induced the appearance of Dk protozoa. In treated cells, the kinetoplast lost its normal disc-shaped structure because the fibrillar arrangement was reduced to a compact, amorphous mass within the mitochondrion. Moreover, basic proteins associated with kDNA were redistributed throughout the Dk protozoal kinetoplast. We sought to understand how the disruption of the kDNA leads to the emergence of the Dk phenotype with atomic force microscopy (AFM) analysis of isolated networks. Our results demonstrate that the detachment of minicircles from the kDNA disk promotes the disassembly of the network, thereby generating Dk cells. Our data strongly suggest that acriflavine inhibits T. cruzi multiplication by interfering with kDNA replication.
authors: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors: Thiago
authors: T
authors: Manchester
authors: Danielle Pereira
authors: DP
authors: Cavalcanti
authors: Marcelo
authors: M
authors: Zogovich
authors: Wanderley
authors: W
authors: DE Souza
authors: Maria Cristina Machado
authors: MC
authors: Motta
mesh_terms: D000167:Acriflavine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D018105:DNA, Kinetoplast / Q000187:drug effects* / Q000235:genetics; D006651:Histocytochemistry; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: D018105:DNA, Kinetoplast; D000167:Acriflavine