Mitochondria are dynamic organelles forming a specific network by membrane remodeling events according to cellular needs1. Mitochondria contain multiple copies of their own genome, mtDNA, a circular molecule that encodes essential proteins involved in cellular energy production. A reduced levels of mtDNA or pathogenic mutations in the mitochondrial genome have been associated with human diseases. These include inherited primary mitochondrial diseases, as well as age-related conditions like neurodegeneration and cancer. However, the precise mechanisms through which mitochondrial dynamics regulate both the levels and quality control of mtDNA remain not well understood.
The goals of this collaborative project is: (i) to elucidate how mitochondrial dynamics control the regulation of mtDNA copy number and/or its quality and (ii) to engineer tools to visualise different genetic mtDNA variants in living cells. Using recently developed methods of mitochondrial genome editing, we will generate cellular and mouse models of mitochondrial disorders that harbour mtDNA mutations2 and employ state-of-the-art microscopy, mitochondrial function and mtDNA analysis3, to investigate (1) how the manipulation of mitochondrial membrane remodelling events control mtDNA content, (2) how these pathways are involved in mtDNA quality control to reduce mutant mtDNA in cellular and in vivo models, (3) the molecular mechanism regulating these processes; and (4) the implication on mitochondrial function. In addition, we will engineer fluorescent probes to specifically label wild-type or mutant mtDNA in order to monitor their dynamics by live-cell imaging during different cellular stress conditions. Together, the successful candidate will monitor mtDNA dynamics and determine how the regulation of mtDNA quality control/levels, by targeting mitochondrial dynamics, could represent a future potential therapeutic target for pathogenic mtDNA mutations.
This multi-disciplinary project will allow the student to employ a range of experimental procedures including molecular and cellular biology, protein engineering, cutting-edge confocal and super-resolution microscopy to mtDNA and mitochondrial function analysis both in cellulo and in vivo. The student will also apply mtDNA editing technologies to develop novel cellular and mouse models in order to increase the physiological relevance of their findings.
Keywords
General: mitochondrial dynamics, mtDNA, heteroplasmy, microscopy
More specific: Membrane remodelling, mitochondrial disease
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