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A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

Lookup NU author(s): Dr Amy VincentORCiD, Dr Chun ChenORCiD, Dr Tiago Gomes Bernardino Gomes, Dr Valeria Di Leo, Kamil Pabis, Dr David McDonald, Professor Andrew FilbyORCiD, Andrew Fuller, Emeritus Professor Doug Turnbull, Dr Amy Reeve, Dr Conor LawlessORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2024 The AuthorsMitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre.

Publication metadata

Author(s): Vincent AE, Chen C, Gomes TB, Di Leo V, Laalo T, Pabis K, Capaldi R, Marusich MF, McDonald D, Filby A, Fuller A, Lehmann Urban D, Zierz S, Deschauer M, Turnbull D, Reeve AK, Lawless C

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta - Molecular Basis of Disease

Year: 2024

Volume: 1870

Issue: 5

Print publication date: 01/06/2024

Online publication date: 21/03/2024

Acceptance date: 15/03/2024

Date deposited: 17/04/2024

ISSN (print): 0925-4439

ISSN (electronic): 1879-260X

Publisher: Elsevier B.V.


DOI: 10.1016/j.bbadis.2024.167131

PubMed id: 38521420


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