Tissue-Specific Implications of Mitochondrial DNA Maintenance in Health and Disease

Joni Nikkanen

Research output: ThesisDoctoral ThesisCollection of Articles

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.
Original languageEnglish
Awarding Institution
  • University of Helsinki
Supervisors/Advisors
  • Suomalainen Wartiovaara, Anu, Supervisor
Award date7 Oct 2017
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-3687-9
Electronic ISBNs978-951-51-3702-9
Publication statusPublished - 7 Oct 2017
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3112 Neurosciences
  • 3124 Neurology and psychiatry

Cite this

Nikkanen, J. (2017). Tissue-Specific Implications of Mitochondrial DNA Maintenance in Health and Disease. Helsinki: University of Helsinki.
Nikkanen, Joni. / Tissue-Specific Implications of Mitochondrial DNA Maintenance in Health and Disease. Helsinki : University of Helsinki, 2017. 134 p.
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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.",
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Tissue-Specific Implications of Mitochondrial DNA Maintenance in Health and Disease. / Nikkanen, Joni.

Helsinki : University of Helsinki, 2017. 134 p.

Research output: ThesisDoctoral ThesisCollection of Articles

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T1 - Tissue-Specific Implications of Mitochondrial DNA Maintenance in Health and Disease

AU - Nikkanen, Joni

PY - 2017/10/7

Y1 - 2017/10/7

N2 - 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.

AB - 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.

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KW - 3124 Neurology and psychiatry

M3 - Doctoral Thesis

SN - 978-951-51-3687-9

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

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Nikkanen J. Tissue-Specific Implications of Mitochondrial DNA Maintenance in Health and Disease. Helsinki: University of Helsinki, 2017. 134 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 55/2017).