Polymorphism and Mitochondrial Activity In Sleeping Sickness Trypanosomes

Vickerman, K.

doi:10.1038/208762a0

Cited by 285 publications

(152 citation statements)

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“…Because the kinetoplast is maintained at a specific position yet the single mitochondrion extends along the length of the cell (Vickerman, 1965;Simpson, 1972;Vickerman et al, 1988), there is a strong suggestion that some structure links the kDNA within the mitochondrial lumen to a particular position on the inner mitochondrial membrane. Moreover, this structure should presumably be positioned directly opposite the basal bodies.…”

Section: Unilateral Kinetoplast Filaments Of Tacmentioning

confidence: 99%

A High-OrderTrans-Membrane Structural Linkage Is Responsible for Mitochondrial Genome Positioning and Segregation by Flagellar Basal Bodies in Trypanosomes

Ogbadoyi

Robinson

Gull

2003

MBoC

234

279

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In trypanosomes, the large mitochondrial genome within the kinetoplast is physically connected to the flagellar basal bodies and is segregated by them during cell growth. The structural linkage enabling these phenomena is unknown. We have developed novel extraction/fixation protocols to characterize the links involved in kinetoplast-flagellum attachment and segregation. We show that three specific components comprise a structure that we have termed the tripartite attachment complex (TAC). The TAC involves a set of filaments linking the basal bodies to a zone of differentiated outer and inner mitochondrial membranes and a further set of intramitochondrial filaments linking the inner face of the differentiated membrane zone to the kinetoplast. The TAC and flagellum-kinetoplast DNA connections are sustained throughout the cell cycle and are replicated and remodeled during the periodic kinetoplast DNA S phase. This understanding of the high-order trans-membrane linkage provides an explanation for the spatial position of the trypanosome mitochondrial genome and its mechanism of segregation. Moreover, the architecture of the TAC suggests that it may also function in providing a structural and vectorial role during replication of this catenated mass of mitochondrial DNA. We suggest that this complex may represent an extreme form of a more generally occurring mitochondrion/cytoskeleton interaction. INTRODUCTIONThe African trypanosome Trypanosoma brucei belongs to a large order of pathogenic and free-living flagellated protozoa designated the kinetoplastida. The majority of these organisms possess a single mitochondrion containing a structural mass of proteins and catenated circular DNA molecules, the kinetoplast. The kinetoplast is essential for survival and cyclical transmission of the parasite between mammalian host and tsetse fly. Early light microscope descriptions of trypanosomes recognized the precise location of the kinetoplast in proximity to the base of the flagellum (Robertson, 1912(Robertson, , 1913. The positions of the flagellum and kinetoplast have become the central features in classifying the different life cycle stages of kinetoplastids (Hoare and Wallace, 1966;Vickerman, 1976). Electron microscopy revealed the kinetoplast to be a highly complex disk-shaped structure located within a distended portion of the mitochondrial matrix adjacent to the flagellum basal bodies (Vickerman, 1973). The T. brucei kinetoplast consists of multiple copies of topologically interlocked circular DNA molecules termed maxicircles and minicircles, along with specific kinetoplast proteins. The maxicircle composition of the T. brucei network is 25-50 copies and represents 10% of the network mass (each maxicircle is 20 kb and all have identical DNA sequence). Maxicircles encode the mitochondrial proteins and some guide RNAs (gRNAs), whereas the minicircles are present in several thousand copies (1 kb in length), are heterogeneous in sequence, and encode gRNAs. The gRNAs are essential for the RNA editing process whereby the maxic...

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Section: Unilateral Kinetoplast Filaments Of Tacmentioning

confidence: 99%

A High-OrderTrans-Membrane Structural Linkage Is Responsible for Mitochondrial Genome Positioning and Segregation by Flagellar Basal Bodies in Trypanosomes

Ogbadoyi

Robinson

Gull

2003

MBoC

234

279

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“…In T. brucei, as in all members of the Trypanosomatid family, the first part of this pathway is catalyzed in a subcellular organelle called a 'glycosome ' [4]. This highly specialized microbody contains all the enzymes required for the conversion of glucose and glycerol into 3- When, after a second bite by the tsetse fly, the trypanosome is reintroduced into the fly midgut a metabolic switch takes place, which leads to an important reduction in the rate of glycolysis and a derepression of rnitrochondrial activity [7]. The amounts of several glycolytic enzymes are decreased [8], whereas phosphoglycerate kinase, almost entirely associated with glycosomes in the vertebrate stage, is now predominantly found in the cytosol [9].…”

mentioning

confidence: 99%

The phosphoglycerate kinases from Trypanosoma brucei

Misset

Opperdoes

1987

European Journal of Biochemistry

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Trypanosoma brucei has two phosphoglycerate kinase (PGK) isoenzymes, one is particle-bound and localized in glycosomes while the other is present in the cytosol. The cytosolic isoenzyme (cPGK) was 900-fold purified from cultured procyclic trypanosomes by hydrophobic interaction chromatography on phenyl-Sepharose followed by affinity chromatography on 2,3'-ATP-Sepharose and had a specific activity of 275 units/mg protein. cPGK was compared with the purified glycosomal isoenzyme (gPGK) from bloodstream-form trypanosomes as well as with the commercially available PGKs from yeast, rabbit muscle and Spirulina platensis, a blue-green alga.Like all other PGKs, cPGK was a monomeric protein with a molecular mass of approximately 45 kDa similar to that of the PGKs from other organisms but 2 kDa smaller than that of gPGK. Despite thls difference in length and a great difference in isoelectric point, the two trypanosome isoenzymes strongly resembled each other in several respects. (a) The kinetic parameters did not differ significantly from each other or from the PGKs of other organisms. (b) Both trypanosome enzymes resembled the enzyme from S . platensis in that they had an almost absolute requirement for ATP, contrary to the enzymes from yeast and rabbit muscle, which were capable of utilizing GTP and ITP also. This difference in substrate specificity may be related to the amino acid substitutions, Trp 308-His and Ala 306-+Glu in the adenine-binding site, which are only found in the two Trypanosoma isoenzymes. Kinetic analysis showed that these substitutions do not prevent binding of the ATP analogoues, but probably prevent phosphoryl-group transfer. (c) Both isoenzymes displayed an activity optimum at pH 6.0 -9.0 similar to that for the enzyme of yeast.Both gPGK and cPGK were inhibited by the trypanocidal drug Suramin. This inhibition could be described as competitive both with ATP and 3-phosphoglycerate with two inhibitor molecules binding to one molecule of enzyme. The gPGK, however, was much more sensitive (KYPP, = 8.0 pM) to Suramin than either the cPGK (KrPP. = 20 pM) or the enzymes from rabbit muscle (KrPP. = 55 pM), yeast (KrPP. = 167 pM) or S . platensis (KrPP. = 250 pM). It is suggested that positive charges on the enzyme's surface may play an important role in the potentiation of the binding of the negatively charged Suramin molecule.Trypanosoma brucei, a protozoan haemoflagellate belonging to the order Kinetoplastida, undergoes a complex life cycle comprising vertebrate and insect stages. When the parasite grows in the midgut of the tsetse fly, mitochondrial metabolism is fully active, involving a functional Kreb's cycle and cytochromes [l]. These trypanosomes mainly utilize amino acids [2]. However, when introduced into the mammalian bloodstream upon the infective bite of a fly it is the long slender bloodstream form, completely lacking mitochondrial activity [l], that develops in the host. In the vertebrate stage glycolysis is the only ATP-generating pathway available, producing two molecules of ATP for each...

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“…Some strains proved to be highly pleomorphic (50 percent stumpy forms) even in clones (Miles, 1970). Miles (1972) also demonstrated that the mito chondrial marker enzyme, NAD diaphorase, was found in the short form of T. evansi SAK strain suggesting that the stumpy forms in this species correspond physiologically to those of T. brucei (Vickerman, 1965).…”

Section: Resultsmentioning

confidence: 88%

Multinuclear forms in a dyskinetoplastic strain ofTrypanosoma evansiin mice

Lun¹,

Vickerman

1991

Ann. Parasitol. Hum. Comp.

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SummaryThe production of short stumpy and multinuclear trypanosomes in a Chinese strain of dyskinetoplastic Trypanosoma evansi main tained in rabbits and mice is described. Production of multinu clear trypanosomes was increased following passage through a rep tile (gecko), in which the trypanosomes did not multiply, and transfer back to mice. The multinuclear trypanosomes showed more nuclei than flagella indicating that disruption of the normal cell cycle had taken place and not simply inhibition of cleavage. A Chinese kinetoplastic T. evansi treated similarly rarely produced stumpy or multinuclear forms.Résumé : Production, par une souche dyskinétoplastique de Trypanosoma evansi, de formes multinucléées chez la souris.La production de formes trypanosomes courtes, trapues et pluri nucléées, par une souche diskinétoplastique de Trypanosoma evansi, maintenue par passages chez lapins et souris, est décrite. La pro duction de trypanosomes plurinucléés a augmenté à la suite du passage par un gecko (chez lequel les trypanosomes ne se sont pas multipliés), puis transfert à nouveau sur souris. Les trypano somes plurinucléés présentent plus de noyaux que de flagelles, ce qui indique une anomalie du cycle cellulaire et non une simple inhibition de la bipartition. Une souche chinoise kinétoplastique de T. evansi ayant subi les mêmes manipulations ne produit que rarement des formes trapues ou plurinucléées.

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Polymorphism and Mitochondrial Activity In Sleeping Sickness Trypanosomes

Cited by 285 publications

References 31 publications

A High-OrderTrans-Membrane Structural Linkage Is Responsible for Mitochondrial Genome Positioning and Segregation by Flagellar Basal Bodies in Trypanosomes

A High-OrderTrans-Membrane Structural Linkage Is Responsible for Mitochondrial Genome Positioning and Segregation by Flagellar Basal Bodies in Trypanosomes

The phosphoglycerate kinases from Trypanosoma brucei

Multinuclear forms in a dyskinetoplastic strain ofTrypanosoma evansiin mice

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