Abstract The mitochondrial genome encodes core subunits involved in the process of oxidative phosphorylation. The sequence and structure of these mitochondria-encoded polypeptides are expected to be shaped by bioenergetic requirements linked to diet and environment. Here, we have developed a robust and effective method for highlighting phylogenetic tree edges with unexpectedly rapid, and likely consequential, substitutions within mitochondrial proteins. Further, our approach allows detection of discrete protein substitutions likely to alter enzyme performance. A survey of mammalian taxonomic groups performed using our method indicates that widely conserved residues in mitochondria-encoded proteins are more likely to rapidly mutate toward variants providing lower OXPHOS activity within specific clades. Intriguingly, our data suggest reduced cellular metabolism of ancestral anthropoids, and our findings have potential implications regarding primate encephalization. Significance Statement Mitochondria harbor DNA (mtDNA) that encodes proteins important for converting food into energy. The environment and lifestyle of an organism shapes, and is shaped by, the sequences of these mitochondrial genomes. We developed a new approach for the detection of rapid functional change to proteins, and we applied our method to the mitochondria-encoded polypeptides of mammals. We found that primates displayed a general signature of relative hypometabolism that is shared with other mammals characterized by a low metabolic rate. Indications of reduced cellular metabolism extend even to the earliest anthropoids. Our findings have potential implications regarding the evolution of an enlarged primate brain.

A novel approach to the detection of unusual mitochondrial protein change suggests low basal metabolism of ancestral anthropoids