Proteomics of Cytochrome c Oxidase-Negative versus -Positive Muscle Fiber Sections in Mitochondrial Myopathy.

Murgia, Marta; Klopstock, Thomas; Tan, Jing; Mann, Matthias; Geyer, Philipp E; Doll, Sophia

doi:10.1016/j.celrep.2019.11.055

Journal Article

DZNE-2020-00032

Proteomics of Cytochrome c Oxidase-Negative versus -Positive Muscle Fiber Sections in Mitochondrial Myopathy.

Murgia, M. ; Tan, J. ; Geyer, P. E. ; Doll, S. ; Mann, M. (Corresponding author) ; Klopstock, T. (Last author)DZNE*

2019
Elsevier [New York, NY]

Cell reports 29(12), 3825-3834.e4 (2019) [10.1016/j.celrep.2019.11.055]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2019.11.055

Abstract: The mosaic distribution of cytochrome c oxidase+ (COX+) and COX- muscle fibers in mitochondrial disorders allows the sampling of fibers with compensated and decompensated mitochondrial function from the same individual. We apply laser capture microdissection to excise individual COX+ and COX- fibers from the biopsies of mitochondrial myopathy patients. Using mass spectrometry-based proteomics, we quantify >4,000 proteins per patient. While COX+ fibers show a higher expression of respiratory chain components, COX- fibers display protean adaptive responses, including upregulation of mitochondrial ribosomes, translation proteins, and chaperones. Upregulated proteins include C1QBP, required for mitoribosome formation and protein synthesis, and STOML2, which organizes cardiolipin-enriched microdomains and the assembly of respiratory supercomplexes. Factoring in fast/slow fiber type, COX- slow fibers show a compensatory upregulation of beta-oxidation, the AAA+ protease AFG3L1, and the OPA1-dependent cristae remodeling program. These findings reveal compensatory mechanisms in muscle fibers struggling with energy shortage and metabolic stress.

Keyword(s): Adult (MeSH) ; Case-Control Studies (MeSH) ; Computational Biology (MeSH) ; Electron Transport Complex IV: metabolism (MeSH) ; Energy Metabolism (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Mitochondrial Myopathies: metabolism (MeSH) ; Mitochondrial Myopathies: pathology (MeSH) ; Muscle, Skeletal: metabolism (MeSH) ; Proteome: analysis (MeSH) ; Proteome: metabolism (MeSH) ; Proteomics: methods (MeSH) ; Single-Cell Analysis: methods (MeSH) ; Stress, Physiological (MeSH)