Tissue-Specific Implications of Mitochondrial DNA Maintenance in Health and Disease
Year: 2017
Type: dissertation
Abstract: Defects of mitochondrial DNA (mtDNA) replication underlie common metabolic disorders. Despite mtDNA is degraded and synthesised in all cells containing mitochondria, mtDNA replication stress typically causes generation of mtDNA deletions or depletion of mtDNA copy number in muscle and brain, which manifest as mitochondrial myopathy (MM) or neurodegeneration, respectively. MtDNA replication defects, however, do not affect highly proliferative tissues, such as blood or intestine, despite their reliance on robust mtDNA replication to sustain high rates of proliferation. The mechanisms behind the tissue-specific manifestations of mtDNA replication defects remain unknown. In this thesis, we aimed to identify the metabolic response pathways for mtDNA replication stress caused by a dominant Twinkle mtDNA helicase (TWNK) mutation leading to adult-onset MM. The study revealed that MM induces a metabolic stress response in muscle which we found to be orchestrated by one master regulator, mechanistic target of rapamycin complex I (mTORC1). The mTORC1-mediated stress response appeared to promote disease progression, and an mTORC1 inhibitor, rapamycin, remarkably improved the mitochondrial muscle disease. It ameliorated the typical hallmarks of MM: the number of ragged red fibers (RRFs) and the amount of mtDNA deletions were reduced after rapamycin treatment. In the second part of this thesis, we studied the transcription regulation of mtDNA replication machinery. We identified a complex regulatory locus for DNA polymerase gamma (POLG) by in silico predictions, which were verified in vivo. The regulatory non-coding locus drives POLG expression specifically in the sensory interneurons of the spinal cord and oculomotor nucleus, which we found to degenerate in POLG patients. The death of these neurons might be the underlying cause of sensory neuropathy and progressive external ophthalmoplegia (PEO), which are typical clinical findings in POLG disorders. The identified regulatory locus is the first non-coding locus for a mitochondrial disease gene and offers the first candidate region for pathogenic non-coding mutations. In conclusion, our work has identified novel contributors in the tissue-specific manifestations of mitochondrial diseases and offers multiple novel treatment targets for mitochondrial disorders, which currently lack effective treatment options.
Source: Työväentutkimus Vuosikirja
Author: Joni Nikkanen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2758588677