<p>Mitonuclear disequilibrium (MTD), defined as the non-random association of nuclear and mitochondrial alleles, is a form of gametic disequilibrium that may arise from coevolutionary adaptation between nuclear and mitochondrial genes interacting to maintain the efficiency of mitochondrial function. Intrinsic and extrinsic factors influence the outcome of this evolutionary process in which compatible alleles of the nuclear and mitochondrial counterparts are co-selected during population divergence. In humans, MTD has not been investigated deeply. Here, we present a genome-wide high-resolution analysis of 2,490 previously published human genomes from the 1000 Genomes Project database. By combining formal testing and simulations to discard random and population effects, we identified 669 nuclear protein-coding genes under MTD. In this set, we found enrichment in functional characteristics, indicating the biological meaningfulness of these genes. Genes with predicted signal peptides for mitochondrial import and genes with directional selection signals were overrepresented. Most genes were population-specific, suggesting a rapid and flexible mechanism of mitonuclear adaptation. The enriched GO terms were related to neurological function, highlighting the significant role and plasticity of neurological genes in the relatively rapid adaptation of mitochondrial function in human evolution.</p>