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
type: CreativeWork
description: 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. V…
abstract: 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. V…
author: Clinton, Tiffany Adelia
language: en
date published: 2026-03
date modified: 2026-07-24T04:40:09Z
provider: Stellenbosch University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Stellenbosch : Stellenbosch University