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Biogénesis de la mitocondria durante el ciclo celular y sus alteraciones en cáncer
|Advisor:||Cuezva, José M.|
|Publisher:||Universidad Autónoma de Madrid|
|Abstract:||Mitochondria play essential roles in cellular energetic metabolism, the execution
of cell death and intracellular calcium and reactive oxygen species signalling. A growing
number of human diseases are nowadays associated with the molecular and/or functional
alteration of mitochondria. The results reported in this thesis emphasize the role of the
mitochondria in cancer biology. In this regard, Otto Warburg reported, as early as in 1924,
that the glycolytic phenotype of tumors results from mitochondrial malfunction in the
cancer cell. However, his hypothesis has been basically neglected until recently. Herein,
we have studied in normal and tumor biopsies derived from the same patients the changes
in the expression level of bioenergetic and structural mitochondrial proteins concurrently
with the expression of glycolytic markers of the cell, the so-called “bioenergetic signature”.
In agreement with previous findings in other carcinomas, the results obtained in squamous
carcinomas of the oesophagus support the original Warburg hypothesis because we observed
a reduction of the bioenergetic competence of the organelle when compared to normal
oesophageal tissue. In contrast, in prostate adenocarcinomas we observed no alterations
of the bioenergetic signature what might suggest that carcinogenesis affects the phenotype
of mitochondria in a tissue-specific manner. The finding of an alteration in the metabolic
proteome of cancer as a common feature of most type of carcinomas led us to consider
the “bioenergetic signature” as a tool for the diagnosis and prognosis of cancer patients.
Indeed, the use of these markers of metabolism allowed the molecular discrimination
of melanomas from its metastasis as well as a group of melanoma patients with worse
prognosis. Furthermore, the β-F1/GAPDH ratio provided a significant marker of disease
progression for melanoma patients.
From the mechanistic point of view, we have studied the effect of oncogenes (RAS,
PDGF, AKT and EBV) on the “bioenergetic signature” and rates of cellular glycolysis.
We find a variable effect of the different oncogenes in the energetic metabolism of the
cell illustrating that tumor progression is linked to changes in the bioenergetic phenotype
obtaining that tumor progression selects apparently cells with a higher glycolytic
Since it appears that alterations in mitochondrial physiology contribute to the Warburg effect, a question arises: which is the advantage and mechanistic contribution of the downregulation of oxidative phosphorylation for the cancer cell? In this regard, we show that the activity of the H+-ATP synthase participates in the execution of cell death by controlling the generation of reactive oxygen species which in turn promote a severe oxidative damage to mitochondrial proteins, favouring in this way the release of apoptogenic molecules from the organelle. These results provide an additional evidence linking metabolism to cell death and support strongly that the acquisition of a Warburg phenotype is another strategy of cancer cells in order ensure its perpetuation. Our knowledge of the basic cell biology and on the timing and mechanism that control the biosynthesis of mitochondrial constituents during progression through the cell cycle of mammalian cells remain largely unknown. In this work we document the timing of the biosynthesis of different mitochondrial constituents during progression through the cell cycle and illustrate the relevance of the control of translation for appropriate biogenesis of mitochondria. In this regard, we show that the 3’UTR of β-mRNA controls the synthesis of the protein at G2/M, a stage when full development of the mitochondrial membrane potential is attained. Moreover, we document the dynamics and morphological changes experimented by mitochondria during mitosis. A long-standing dogma of cellular and evolutionary biology has been that H+-ATP synthases of F-type are exclusively present in the inner membrane of mitochondria of cell of mammals. However, recent reports claim that this complex is localised at the plasma membrane of human hepatocytes and tumor and endothelial cells. Here we show, using four different antibodies raised against the β-chain of the mitochondrial H+-ATP synthase, and various immunolocalitation techniques and subcellular fractionation experiments, that there is no molecular evidence that could support an ectopic expression of the β-chain on the cell-surface of these cells.
|Description:||Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de consulta: 29-02-2008|
|Appears in Collections:||(CBM) Tesis|