La Trobe

Characterisation of Mitochondrial Complex I Assembly factors in biogenesis and disease

Download (9.52 MB)
thesis
posted on 2023-01-18, 15:35 authored by Luke Formosa
Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora.

Mitochondria play a critical role in most eukaryotic cells as they contribute to a number of different processes, including ATP generation. The mitochondrial inner membrane houses 5 multi-subunit complexes, which together are known as the Oxidative Phosphorylation System and together generate a membrane potential that powers ATP production. The first enzyme in this process is known as NADH:Ubiquinone Oxidoreductase (Complex I) that is composed of 45 subunits and is approximately 1 MDa in size. This enzyme transfers electrons from NADH to ubiquinone, which is coupled to the translocation of protons across the membrane and so contributes to the mitochondrial membrane potential. Mitochondrial disease affects approximately 1 in 5000 live births and one third of these are diagnosed with an isolated Complex I deficiency, making this the most common cause of mitochondrial dysfunction. Defects in Complex I can be caused by mutations in the structural subunits of the enzyme as well as assembly factors involved in Complex I biogenesis. The work presented in this thesis has utilised genome editing techniques coupled to Blue-Native PAGE, proteomics and other biochemical techniques to characterise the role of assembly factors in the Complex I assembly process. The role of the putative Complex I assembly factor FOXRED1 was investigated and was shown to be required for efficient Complex I biogenesis at a late stage of the assembly pathway. Also, biochemical and cellular approaches were employed to provide new insights into the individual roles played by various members of the Mitochondrial Complex I Assembly (MCIA) complex. From this, additional components of the Complex I assembly machinery were postulated. This serves to increase our understanding of Complex I biogenesis and defects in disease.

History

Center or Department

College of Science, Health and Engineering. La Trobe Institute for Molecular Science. Department of Biochemistry and Genetics.

Thesis type

  • Ph. D.

Awarding institution

La Trobe University

Year Awarded

2016

Rights Statement

This thesis contains third party copyright material which has been reproduced here with permission. Any further use requires permission of the copyright owner. The thesis author retains all proprietary rights (such as copyright and patent rights) over all other content of this thesis, and has granted La Trobe University permission to reproduce and communicate this version of the thesis. The author has declared that any third party copyright material contained within the thesis made available here is reproduced and communicated with permission. If you believe that any material has been made available without permission of the copyright owner please contact us with the details.

Data source

arrow migration 2023-01-10 00:15. Ref: latrobe:41948 (9e0739)

Usage metrics

    Open Theses

    Categories

    No categories selected

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC