The mitochondrial network produces the bulk part of the energy mammalian cells need through the oxidative phosphorylation process. The importance of mitochondria is underscored by the fact that deficient oxidative phosphorylation causes a wide number of genetic diseases. It is also heavily implicated in age-associated disease and ageing. Expression of mammalian mtDNA is of key importance for maintaining mitochondrial oxidative phosphorylation but studies of the poorly understood regulation of mammalian mitochondrial gene expression offer substantial experimental challenges. In the late 1990s, we felt that the challenges associated with understanding mammalian mtDNA gene expression could only be tackled by a broad interdisciplinary scientific approach. We therefore started collaboration between the Larsson (expertise in mouse genetics, in vivo physiology and cell biology) and Gustafsson laboratories (expertise in biochemistry, recombinant in vitro systems, structural biology) that has been ongoing for more than a decade. The success of this collaborative effort is documented by many joint publications in high-profile journals. Most importantly, we have together molecularly defined the basal mtDNA transcription initiation machinery and discovered a novel repressor, MTERF3, of mtDNA transcription. In this proposal, we present a series of unpublished results showing quite unexpected complexity in the regulation of mtDNA expression. An important part of our proposed work will be to establish how the different levels of regulation of mtDNA gene expression communicate to achieve a coordinated response to physiological stimuli.
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