Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of
proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC
proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC
protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear
DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)
DNA-encoded subunits. Moreover,
mtDNA copy number was unrelated to
mtDNA-encoded subunits abundance, suggesting that
mtDNA content is not limiting.
Alzheimer's disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower
mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.