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

Cell Rep. 2019 Dec 17;29(12):3825-3834.e4. doi: 10.1016/j.celrep.2019.11.055.


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.

Keywords: COX; CPEO; chronic progressive external ophthalmoplegia; cytochrome c oxidase; laser microdissection; mass spectrometry; mitochondrial myopathy; proteomics; single muscle fibers.

MeSH terms

  • Adult
  • Case-Control Studies
  • Computational Biology
  • Electron Transport Complex IV / metabolism*
  • Energy Metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mitochondrial Myopathies / metabolism*
  • Mitochondrial Myopathies / pathology*
  • Muscle, Skeletal / metabolism*
  • Proteome / analysis*
  • Proteome / metabolism*
  • Proteomics / methods*
  • Single-Cell Analysis / methods
  • Stress, Physiological


  • Proteome
  • Electron Transport Complex IV