Writing in Nature Metabolism, Guhathakurta et al. provide pertinent functional and mechanistic insight about this elusive role. Initially using inducible knockouts in primary mouse embryonic fibroblasts (MEFs), the authors show that loss of MOF or KANSL2 leads to aberrant cellular respiration, excessive mitochondrial reactive oxygen species (mtROS) and reduced mitochondrial potential, concomitantly with a loss of mitochondrial structural integrity. In line with the impaired cristae density in cells lacking the MOF–KANSL complex, the authors observe reduced assembly of the respiratory chain supercomplex, most strongly of complex IV.