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.