- In humans, oxidative phosphorylation (OXPHOS), the cellular energy producer, harbors ~90 nuclear DNA (nDNA)- and mitochondrial DNA (mtDNA)-encoded subunits. Although nDNA- and mtDNA-encoded OXPHOS proteins physically interact, their transcriptional regulation profoundly diverges, thus questioning their co-regulation. To address mtDNA-nDNA gene co-expression, we analyzed ~8,500 RNA-seq Gene-Tissue-Expression (GTEx) experiments encompassing 48 human tissues. We found overall positive cross-tissue mtDNA-nDNA OXPHOS gene co-expression. Nevertheless, alternatively-spliced variants, as well as certain OXPHOS genes, did not converge into the main OXPHOS gene cluster, suggesting tissue-specific flavor of OXPHOS gene expression. Finally, unlike non-brain body sites, and neocortex and cerebellum (‘mammalian’ brain), negative mito-nuclear expression correlation was found in the hypothalamus, basal ganglia and amygdala (‘ancient’ brain). Analyses of co-expression, DNase-seq and ChIP-seq experiments identified candidate RNA-binding genes and CEBPb as best explaining this phenomenon. We suggest that evolutionary convergence of the ‘mammalian’ brain into positive mtDNA-nDNA OXPHOS co-expression reflects adjustment to novel bioenergetics needs.