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Does primary very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency cause secondary defects in mitochondrial oxidative phosphorylation?

thesis
posted on 2019-11-08, 00:00 authored by Hayley Clark
Very long-chain acyl-coA dehydrogenase (VLCAD) is responsible for catalysing the first step in the fatty acid β-oxidation (FAO) pathway. Deficiencies associated with VLCAD result in an energy deficit, as the FAO and oxidative phosphorylation (OXPHOS) pathways of the mitochondria are critical for energy production. VLCAD deficiency is associated with a variable phenotype, often involving cardiomyopathy, heart arrythmias, hepatic failure and sudden unexplained death. While VLCAD deficiency primarily disrupts FAO, secondary defects in oxidative phosphorylation (OXPHOS) may also contribute to disease pathogenesis, with physical interactions between VLCAD and OXPHOS proteins postulated in previous research. Therefore, secondary biochemical and physical defects of the OXPHOS pathway were investigated in VLCAD deficient fibroblasts to determine if they contribute to disease pathogenesis. Aspects of disease pathophysiology examined included OXPHOS complex assembly and stability, mitochondrial reactive oxygen species (ROS) production and cellular respiration.
VLCAD deficiency was not found to affect OXPHOS complex assembly or stability. Increased cellular ROS production was detected in VLCAD deficient cells compared to controls, with ROS generation in VLCAD deficient cells also associated with increased sensitivity to OXPHOS inhibition. VLCAD deficiency was not found to impair basal mitochondrial respiration, in fact, an increase was observed in a potential compensatory mechanism. Overall, the findings suggest that VLCAD deficient cells may have an enhanced anti-oxidant response to compensate for increased ROS production, potentially from complex III. These findings may indicate a novel disease-specific mechanism which, following further investigation, would strengthen our understanding of VLCAD deficiency pathogenesis in hope of expanding treatment options.

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Pagination

63 p.

Material type

thesis

Resource type

thesis

Language

eng

Degree type

Honours

Degree name

B.Science (Hons

Copyright notice

All rights reserved

Editor/Contributor(s)

M McKenzie

Faculty

Faculty of Science

School

Engineering and Built Environment

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