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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Mitochondrial metabolism in cancer transformation and progression

Gaude, Edoardo January 2018 (has links)
Cancer cells undergo a multifaceted rewiring of cellular metabolism to support their biosynthetic needs. Although the major determinants of this metabolic transformation have been elucidated, their broad biological implications and clinical relevance are unclear. In this study, I systematically analysed the expression of metabolic genes across 20 different cancer types and investigated their impact on clinical outcome. I found that cancers undergo a tissue-specific metabolic rewiring, which converges towards a common metabolic landscape. Of note, downregulation of mitochondrial genes is associated with the worst clinical outcome across all cancer types and correlates with the expression of epithelial-to-mesenchymal transition (EMT) gene signature, a feature of invasive and metastatic cancers. Consistently, suppression of mitochondrial genes is identified as key metabolic signature of metastatic melanoma and renal cancer, and metastatic cell lines. This comprehensive analysis reveals unexpected facets of cancer metabolism, with important implications for cancer patients stratification, prognosis, and therapy. I then investigated how mitochondrial dysfunction could affect cell behaviour. I capitalised on a recently developed in vitro cell model with increasing levels of m.8993T > G mutation heteroplasmy. I found that impaired utilisation of reduced nicotinamide adenine dinucleotide (NADH) by the mitochondrial respiratory chain leads to cytosolic reductive carboxylation of glutamine as a new mechanism for cytosol-confined NADH recycling supported by malate dehydrogenase 1 (MDH1). This metabolic coupling is facilitated by the formation of a multienzymatic complex between MDH1 and GAPDH. Importantly, such metabolic coupling between glutamine metabolism and cytosolic NADH recycling is able to support increased glycolytic flux, an important hallmark of cells with dysfunctional mitochondria, as well as cancer cells. Finally, increased glycolysis in cells with mitochondrial dysfunction is associated with enhanced cell migration, in an MDH1-dependent fashion. These results describe a novel link between glycolysis and mitochondrial dysfunction, and uncover potential targets for cells that rely on aerobic glycolysis for proliferation and migration, such as cancer cells.
2

Mitochondrial quality control regulation by small GTPase RAB20

Nayak, Sunayana Govind 19 September 2022 (has links)
No description available.

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