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From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions
Thesis (MSc)--Stellenbosch University, 2026.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2026
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| _version_ | 1867613932015845376 |
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| access_status_str | Open Access |
| author | Clinton, Tiffany Adelia |
| author2 | Pearce, Brendon Clive |
| author_browse | Clinton, Tiffany Adelia Pearce, Brendon Clive |
| author_facet | Pearce, Brendon Clive Clinton, Tiffany Adelia |
| author_sort | Clinton, Tiffany Adelia |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2026. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/135693 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:43:59.926Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2026 |
| publishDateRange | 2026 |
| publishDateSort | 2026 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/135693 From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions Clinton, Tiffany Adelia Pearce, Brendon Clive Stellenbosch University. Faculty of Science. Dept. of Genetics. Thesis (MSc)--Stellenbosch University, 2026. Clinton, T. A. 2026. From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/7d6ca9c7-7fbd-4c56-9e11-b67b1f1f5d9f Non-communicable diseases (NCDs), including Type 2 Diabetes Mellitus (T2DM) and Degenerative Disc Disease (DDD), represent major contributors to global morbidity and mortality, particularly within low- and middle-income countries where aging populations and chronic metabolic stress intersect. Increasing evidence identifies mitochondrial dysfunction as a shared mechanistic pathway underlying both metabolic and degenerative disease processes. Mitochondrial DNA (mtDNA), which encodes essential structural subunits of the electron transport chain (ETC) as well as critical non-coding RNAs, plays a central role in cellular bioenergetics, however, the structural consequences of pathogenic mitochondrial single nucleotide variants (SNVs) remain incompletely characterized, especially in South African populations that are substantially underrepresented in global genomic datasets. This study aimed to investigate how pathogenic mtDNA variants influence mitochondrial structure and function, to mechanistically relate these effects to T2DM and DDD pathology, and to translate structural findings into a framework for targeted supportive intervention. An integrated in silico pipeline was applied to 84 mitochondrial SNVs identified through systematic literature review. Structural modelling was performed across protein-coding genes, non-protein-coding regions, and mitochondrial transfer RNAs using AlphaFold-based prediction, RNA structural modelling, and quantitative structural comparison approaches. Protein–protein interaction (PPI) modelling further evaluated the impact of variants on respiratory chain complex assembly and interface stability. Across mitochondrial respiratory complexes I, III, IV, and V, pathogenic variants predominantly produced localized conformational strain and subunit misalignment, reflected by increased root mean square deviation (RMSD) values relative to wild type structures. These alterations were predicted to impair complex assembly and catalytic efficiency. Variants within mitochondrial tRNAs and regulatory non-coding regions demonstrated complementary mechanisms of dysfunction, including disrupted secondary and tertiary folding consistent with impaired mitochondrial translation and altered regulation of mtDNA replication and transcription. Collectively, these structural disruptions converge on a hypothesis of reduced ATP production and increased reactive oxygen species generation, potentially providing a mechanistic link between mitochondrial genetic variation, metabolic dysfunction, and intervertebral disc degeneration. To explore clinical relevance, selected pathogenic mtDNA variants were genotyped in a South African case-control cohort. All successfully genotyped loci were monomorphic within the final study population, preventing inferential statistical analysis. These findings are interpreted as reflecting limited cohort size and population-specific allele distribution rather than absence of pathogenic relevance, underscoring the need for larger, ethnically representative South African genomic studies. Based on the identified structural mechanisms, this work further proposes a mitochondria-focused nutritional support framework aimed at mitigating oxidative stress, stabilizing electron transport chain function, and supporting cellular energy metabolism. Overall, this thesis provides structural and preliminary clinical evidence suggesting that mitochondrial SNV pathology may be mediated through structural destabilization and impaired respiratory complex integration, supporting mitochondrial dysfunction as a potential shared mechanistic pathway linking metabolic and degenerative disease, while contributing foundational data for underrepresented South African populations. Masters 2026-04-08T07:25:26Z 2026-04-08T07:25:26Z 2026-03 Thesis https://scholar.sun.ac.za/handle/10019.1/135693 en Stellenbosch University 168 pages : ill. application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Clinton, Tiffany Adelia From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions |
| title | From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions |
| title_full | From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions |
| title_fullStr | From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions |
| title_full_unstemmed | From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions |
| title_short | From Protein Structure to Clinical Strategy: An In silico Investigation of Mitochondrial DNA Mutations in Type 2 Diabetes and Degenerative Disc Disease for Targeted Nutritional Interventions |
| title_sort | from protein structure to clinical strategy an in silico investigation of mitochondrial dna mutations in type 2 diabetes and degenerative disc disease for targeted nutritional interventions |
| url | https://scholar.sun.ac.za/handle/10019.1/135693 |
| work_keys_str_mv | AT clintontiffanyadelia fromproteinstructuretoclinicalstrategyaninsilicoinvestigationofmitochondrialdnamutationsintype2diabetesanddegenerativediscdiseasefortargetednutritionalinterventions |