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A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Jun; Vol. 1870 (5), pp. 167131. Date of Electronic Publication: 2024 Mar 21. - Publication Year :
- 2024
-
Abstract
- Mitochondrial 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.<br />Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael F. Marusich declares receipt of licensing revenues from Abcam and EMD/Millipore on sales of anti-mtDNA-encoded protein antibodies. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Male
Female
Adult
Middle Aged
Mitochondria metabolism
Mitochondria pathology
Mitochondria genetics
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
Muscle Fibers, Skeletal metabolism
Muscle Fibers, Skeletal pathology
Electron Transport Complex IV metabolism
Electron Transport Complex IV genetics
Electron Transport Complex I metabolism
Electron Transport Complex I genetics
Signal Transduction
Mitochondria, Muscle metabolism
Mitochondria, Muscle pathology
Mitochondrial Proteins metabolism
Mitochondrial Proteins genetics
DNA, Mitochondrial metabolism
DNA, Mitochondrial genetics
Oxidative Phosphorylation
Prohibitins
Mitochondrial Diseases metabolism
Mitochondrial Diseases pathology
Mitochondrial Diseases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1870
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 38521420
- Full Text :
- https://doi.org/10.1016/j.bbadis.2024.167131