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Malena, Adriana (2008) Mitochondrial DNA heteroplasmy in muscle cybrids harbouring A3243G Melas mutation. [Ph.D. thesis]

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Abstract (english)

The maternally inherited mitochondrial DNA (mtDNA) A3243G point mutation, in tRNALeu(UUR) gene is associated with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), but it has also been detected in other pathologies, such as cardiomyopathy, maternally inherited diabetes with deafness (MIDD) and progressive external ophtalmoplegia (PEO). Despite the knowledge of the genetic defect that impairs mitochondrial protein synthesis and thereby compromises respiration, a complete understanding of the pathogenesis of MELAS remains elusive. Every cell contains multiple copies of mtDNA and in cells and tissues of patients with this syndrome, mutant and wild-type mtDNA molecules coexist (heteroplasmy).
Clinical status of human mitochondrial disorders associated with heteroplasmic mtDNA mutations is greatly dependent on the residual amount of wild-type mtDNA molecules. No clinical symptoms or biochemical respiratory chain defects are detected above a relatively low threshold of wild-type mtDNA proportion. A "selective advantage" or "dominant factor" of mutant mtDNA molecules is known. In this work we aimed to: i) verify different conditions able to modify the percentage of mutant mtDNA in vitro; ii) try to understand why mutant mtDNA molecules had a selective advantage in cultured muscle cells.
At first heteroplasmic cybrids with a muscular nuclear background harbouring MELAS mutation (RD cybrids) have been established. Different growth regimes (antioxidant supplementation, creatine, uridine, low glucose) were tested to verify an influence on percentage of MELAS mutation, but all failed.
In this work we substantiated the greater survival of muscular heteroplasmic 83% and 92% MELAS cybrids compared to homoplasmic 0% and 99% cells, in energetic stress conditions (5mM glucose instead of 25mM glucose). Physiological, biochemical and molecular analysis indicated that cells with an intermediate mutant load presented an increase of their bioenergetic anaerobic and aerobic pathways. This probably helps the cells to better survive in energetic stress as shown by growth rate and RCR values, concomitant to a reduced ROS generation.
Mitochondrial fusion was favoured through the downregulation of Drp1 and hFis1, proteins involved in mitochondrial fission, using RNAi method. Surprisingly mitochondrial fusion determined the increase of mutant mtDNA molecules in some clones. This result shows that mitochondrial fusion favours mutant mtDNA molecules that are dominant on wild-type in a muscle nuclear background.

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EPrint type:Ph.D. thesis
Tutor:Vergani, Lodovica
Ph.D. course:Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:January 2008
Anno di Pubblicazione:January 2008
Key Words:MELAS, cybrids, heteroplasmy, mitochondrial DNA
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/26 Neurologia
Struttura di riferimento:Dipartimenti > Dipartimento di Neuroscienze
Codice ID:725
Depositato il:08 Oct 2008
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