Influence of mitochondrial and nuclear genomic dysfunction on lipid homeostasis in lipidemic diseases

Intervertebral disc degeneration (DDD) is a multifactorial, age-related disorder and a major contributor to chronic low back pain (LBP) and disability. Its pathogenesis involves extracellular matrix degradation and inflammation, augmented by mitochondrial dysfunction and dysregulated lipid metabolism. DDD and dyslipidaemia are both highly prevalent non-communicable diseases (NCDs) in South African urban populations, with rising incidence rates. Despite these NCDs high prevalence, research in African populations often focuses on lifestyle factors, and so genetic contributions to disease progression remain largely uncharacterised, compounded by limited representation of African cohorts. Therefore, the aim of this study was to investigate associations between mitochondrial and nuclear variants related to mitochondrial dysfunction and lipid metabolism in NCD progression for a South African cohort. To investigate the functional relevance of mitochondrial variation 59 mitochondrial DNA (mtDNA) variants across 11 oxidative phosphorylation genes and 8 nuclear regulatory variants implicated in lipid metabolism were systematically characterised in silico. Protein subunits were assessed in generated models to evaluate structural, physiochemical and stability parameters. Respiratory chain complexes III IV and V were modelled to assess conformation changes and protein-protein interactions and evaluate potential functional consequences within disease states. Overall, structural modelling presented consistent reduced conformational stability and compromised proton and electron transport in the respiratory chain. After in silico analyses, a total of 13 mitochondrial DNA and 8 nuclear encoded variants were selected for genotypic analysis within a South African cohort and association to mitochondrial dysfunction and non-communicable diseases. A case -control cohort was recruited by convenience sampling in the Cape Town metropolitan area. Genotypic data was generated for 138 participants. Population genetic analyses were conducted to assess population structure, identify population-specific variation and test disease associations. In this cohort both monomorphic and polymorphic variants were identified. Although no variant showed statistically significant association with DDD status, cases showed higher mutant allele frequencies at select mitochondrial and nuclear variants. These findings provide preliminary evidence of population specific mitochondrial and nuclear genetic variation in a South African cohort and potentially link mtDNA variants to complex instability and mitochondrial dysfunction in DDD and broader NCDs, within the South African context. This could aid in variant selection and functional validation within a larger cohort.

Grantor dc:publisher

Stellenbosch : Stellenbosch University

Year dc:date.issued

2026

Author dc:creator

• Austin, Robyn Hannah

Advisor dc:contributor.advisor

• Pearce, Brendon

Language dc:language.iso

en

Repository record dc:identifier.uri

https://scholar.sun.ac.za/handle/10019.1/135574

OAI identifier oai:identifier

oai:scholar.sun.ac.za:10019.1/135574