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Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseasesSong, Shiwei 24 February 2005 (has links)
It is well known that the mitochondrial genome has a much higher spontaneous
mutation rate than the nuclear genome. mtDNA mutations have been identified in
association with many diseases and aging. mtDNA replication continues throughout the
cell cycle, even in post-mitotic cells. Therefore, a constant supply of nucleotides is
required for replication and maintenance of the mitochondrial genome. However, it is not
clear how dNTPs arise within mitochondria nor how mitochondrial dNTP pools are
regulated. Recent evidence suggests that abnormal mitochondrial nucleoside and
nucleotide metabolism is associated with several human diseases. Clearly, to uncover the
pathogenesis of these diseases and the mechanisms of mitochondrial mutagenesis,
information is needed regarding dNTP biosynthesis and maintenance within
mitochondria, and biochemical consequences of disordered mitochondrial dNTP
metabolism.
The studies described in this thesis provide important insight into these questions.
First, we found that a distinctive form of ribonucleotide reductase is associated with
mammalian liver mitochondria, indicating the presence of de novo pathway for dNTP
synthesis within mitochondria. Second, we found that long term thymidine treatment
could induce mtDNA deletions and the mitochondrial dNTP pool changes resulting from
thymidine treatment could account for the spectrum of mtDNA point mutations found in
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients. These results
support the proposed pathogenesis of this disease. Third, we found that normal
intramitochondrial dNTP pools in rat tissues are highly asymmetric, and in vitro fidelity
studies show that these imbalanced pools can stimulate base substitution and frameshift
mutations, with a substitution pattern that correlates with mitochondrial substitution
mutations in vivo. These findings suggest that normal intramitochondrial dNTP pool
asymmetries could contribute to mitochondrial mutagenesis and mitochondrial diseases.
Last, Amish lethal microcephaly (MCPHA) has been proposed to be caused by
insufficient transport of dNTPs into mitochondria resulting from a loss-of-function
mutation in the gene encoding a mitochondrial deoxynucleotide carrier (DNC). We found
that there are no significant changes of intramitochondrial dNTP levels in both a MCPHA
patient's lymphoblasts with a missense point mutation in Dnc gene and the homozygous
mutant cells extracted from Dnc gene knockout mouse embryos. These results do not
support the proposed pathogenesis of this disease and indicate that the DNC protein does
not play a crucial role in the maintenance of intramitochondrial dNTP pools. / Graduation date: 2005
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Functional and molecular changes of mitochondria in human aging: observations in dividing tissuesWeng, Shan January 2000 (has links) (PDF)
Studies in a number of human tissues have revealed that the activities of mitochondrial respiratory chain enzyme complexes decline during the aging process. Other studies have suggested that aging increases the frequency of mitochondrial DNA (mtDNA) mutation and leads to the accumulation of mutant mtDNA species, mainly those with large deletions and point mutations. Although the mitochondrial theory of aging may be more applicable to post mitotic tissues, abnormalities of mtDNA have also been reported in tissues which retain a mitotic capacity. Fresh tissues from elderly patients are difficult to obtain and only a limited number of studies on biochemical examination of respiratory chain enzyme complex activities have been carried out. Prostate tissue is readily available in elderly male subjects because of the high prevalence of benign prostatic hypertrophy in this sub-group of the population, and endoscopic surgery is routinely performed for excision of the diseased prostate. In this study, mitochondrial respiratory function and the mtDNA mutations in prostate tissues of elderly patients (aged from 56 to 92) were studied in 24 subjects. This included the measurement of the activities of the respiratory chain enzyme complexes and screening for mitochondrial point mutations and deletions at sites commonly affected in neurodegenerative diseases. (For complete summary open document)
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Mitochondrial DNA heteroplasmy in radiation induced myelodysplasia and leukaemiaLa Cock, Charles J. R. January 1996 (has links)
Thesis (MTech (Medical Technology))--Cape Technikon, 1996. / Haematological defects observed in clonal deletions of mtDNA and
the inhibition of mitochondrial function by benzene and
chloramphenicol, suggest a role for mtDNA in the pathogenesis of
radiation - induced preleukaemia (MDS). The fact that leukaemia
cells contain abnormal mitochondria and abnormally structured
mtDNA, makes it reasonable to assume mtDNA mutations could be
central to the pathogenesis of both MDS and leukaemia. It was
decided to examine MDS patients for the presence of mtDNA length
mutations (dimers and cocantameres). Such topological forms have
already been reported in the literature in association with human
leukaemia. These steric considerations suggest that mtDNA dimers
are probably non-functional due to supercoiling.
Thus, it was
felt that a progressive accumulation of non-functional dimers in
the haematopoietic compartment could account for many of the
clinical features associated with MDS. Transmission electron
microscopy was used to examine haematopoietic mtDNA in the bone
marrow of six patients with MDS. Abnormal mtDNA dimer formation
was found in all instances. The proportional number of these
dimers were found to roughly correlate with the Myeloid/
Erythroid cell ratio in the bone marrow, and it appeared likely
that the dimers were generated in the myeloid compartment during
early MDS.
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Mitochondrial DNA heteroplasmy in radiation induced myelodysplasia and leukaemiaLa Cock, Charles JR January 1996 (has links)
Thesis (MTech(Medical Technology))--Cape Technikon, Cape Town, 1996 / Haematol.ogical defects observed in cl.onal deletions of mtDNA and
the inhibition of mitochondrial function by benzene and
chloramphenicol., suggest a role for mtDNA in the pathogenesis of
radiation - induced preleukaemia (MDS). The fact that leukaemia
cell.s contain abnormal mitochondria and abnormally structured
mtDNA, makes it reasonable to assume mtDNA mutations could be
central to the pathogenesis of both MDS and l.eukaemia. It was
decided to examine MDS patients for the presence of mtDNA length
mutations (dimers and cocantameres). Such topol.ogical forms have
already been reported in the literature in association with human
leukaemia. These steric considerations suggest that mtDNA dimers
are probably non-functional due to supercoil.ing. Thus, it was
felt that a progressive accumulation of non-functional dimers in
the haematopoietic compartment could account for many of the
cl.inical. features associated with MDS. Transmission electron
microscopy was used to examine haematopoietic mtDNA in the bone
marrow of six patients with MDS. Abnormal mtDNA dimer formation
was found in al.l instances. The proportional. number of these
dimers were found to roughly correlate with the Myeloid/
Erythroid cell. ratio in the bone marrow, and it appeared likely
that the dimers were generated in the myeloid compartment during
early MDS.
Control.l.ed radiation studies were performed on 20 wistar rats
in an attempt to elucidate the approximate time when abnormal
mtDNA dimer formation occurred, fol.l.owing fractionated gamma or
gamma-neutron irradiation.
Gamma-irradiated rats demonstrated abnormal mtDNA dimer formation
at the time hypoplastic marrow recovery was first observed.
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Molecular basis of deafness linked to mitochondrial DNA mutationsBallana Guix, Ester 04 May 2007 (has links)
La seqüenciació del genoma humà ha marcat una fita important en la història de la biologia. Com a conseqüència, la genètica i la genòmica han experimentat un progrés enorme. Això ha permès un millor coneixement tant de les causes genètiques de malalties humanes, com del per què de les diferències comunes entre individus. Com a sistemes complexos que som tots els éssers vius, hem de considerar el paper que tenen les interaccions entre les diferents parts del genoma a l'hora d'especificar el resultat final, és a dir, el fenotip. Igualment, podem dir que el genoma conté un conjunt d'instruccions, però que la forma en què aquestes es porten a terme depèn, també de contingències ambientals i històriques. Per tant, la naturalesa de les instruccions genètiques no és completament determinista en tots els casos, si bé hi ha una sèrie de processos en què sí que es compleix aquesta perfecta relació entre herència i expressió final. Aquesta mateixa situació es presenta amb certes alteracions genètiques i amb el desenvolupament de patologies, la qual cosa facilita enormement el diagnòstic precoç i obre les possibilitats per a la teràpia genètica. Però la gran majoria de fenotips, incloent-hi moltes condicions d'interès per a la medicina, tenen una base complexa, és a dir, no existeix "el gen" que determina el caràcter de forma unívoca, sinó que aquest és el resultat de l'acció simultània de molts gens, no tots amb la mateixa participació, juntament amb l'efecte de l'ambient. Aquesta tesi doctoral va arrencar en aquest punt, tenint com a objectiu l'aprofundiment en les bases genètiques d'un tipus de sordesa lligada a mutacions al vi Preface DNA mitocondrial i de la qual se'n tenien evidències de la implicació tant de factors ambientals com diversos factors genètics. D'altra banda, els tests basats en l'ADN són un dels primers usos comercials i d'aplicació mèdica d'aquests nous descobriments de la genètica. Aquests tests poden ser utilitzats per al diagnòstic de malalties, confirmació diagnòstica, informació del pronòstic, així com del curs de la malaltia, confirmar la presència de malaltia en pacients assimptomàtics i amb diferents graus de certesa, predir el risc de futures malalties en persones sanes i en la seva descendència. Aquest és l'objectiu final, i sovint encara utòpic, de la recerca en biomedicina: una millor comprensió del procés biològic, que derivi en un millor tractament i prevenció de la malaltia. Aquesta tesi també ha volgut contribuir humilment en aquest aspecte. Durant aquests anys s'han recollit centenars de mostres de famílies sordes, amb la finalitat de donar un "diagnòstic" de la causa genètica. Poques vegades ho hem conseguit, però en qualsevol cas, si això alguna vegada ha ajudat a algú d'alguna manera, ja em dono per satisfeta.
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