Abstract
Human mitochondrial DNA is a distinct, compact genetic system that encodes proteins crucial for energy metabolism in the cell. Due to its reduced size and relatively simple organisation, all the regulatory factors directing the expression of the mitochondrial genome are encoded by nuclear DNA. It is evident that mitochondrial gene expression is regulated at different levels, which is reflected by the numerous diseases associated with mutations in both nuclear and mitochondrial DNA-encoded mitochondrial proteins. Research focusing on the identification and characterisation of RNA-binding proteins as regulators of mitochondrial function is ongoing. However, the components and mechanisms involved in the post-transcriptional regulation of mitochondrial DNA are not well understood.
The aim of this research project was to investigate different aspects of the regulation of human mitochondrial gene expression via the direct action of nuclear-encoded mitochondrial proteins on RNA metabolism. First, I validated the proteins responsible for 5' end processing of mitochondrial precursor transcripts and identified the protein responsible for 3' end processing cleavage, showing that they are important for mitochondrial function. Next, I studied a previously uncharacterised mitochondrial ribosomal subunit protein and found that it is an important factor in the regulation of protein synthesis. Finally, I examined a protein that has multiple and independent functions in the organelle and identified it as a new target for the estrogenic modulation of mitochondrial gene expression via the estrogen receptor alpha.
Both the nuclear and the mitochondrial genomes contribute to the mitochondrial proteome and hence to mitochondrial function. Because mitochondria possess a genome that is central to multiple cellular functions, understanding the different levels and mechanisms involved in the regulation of mitochondrial gene expression is essential in elucidating the contribution of mitochondrial dysfunction to human disease.
The aim of this research project was to investigate different aspects of the regulation of human mitochondrial gene expression via the direct action of nuclear-encoded mitochondrial proteins on RNA metabolism. First, I validated the proteins responsible for 5' end processing of mitochondrial precursor transcripts and identified the protein responsible for 3' end processing cleavage, showing that they are important for mitochondrial function. Next, I studied a previously uncharacterised mitochondrial ribosomal subunit protein and found that it is an important factor in the regulation of protein synthesis. Finally, I examined a protein that has multiple and independent functions in the organelle and identified it as a new target for the estrogenic modulation of mitochondrial gene expression via the estrogen receptor alpha.
Both the nuclear and the mitochondrial genomes contribute to the mitochondrial proteome and hence to mitochondrial function. Because mitochondria possess a genome that is central to multiple cellular functions, understanding the different levels and mechanisms involved in the regulation of mitochondrial gene expression is essential in elucidating the contribution of mitochondrial dysfunction to human disease.
| Original language | English |
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| Qualification | Doctor of Philosophy |
| Publication status | Unpublished - 2014 |