An evolutionary perspective of AMPK-TOR signaling in the three domains of life.

AMPK and TOR protein kinases are the major control points of energy signaling in eukaryotic cells and organisms. They form the core of a complex regulatory network to co-ordinate metabolic activities in the cytosol with those in the mitochondria and plastids. Despite its relevance, it is still unclear when and how this regulatory pathway was formed during evolution, and to what extent its representations in the major eukaryotic lineages resemble each other. Here we have traced 153 essential proteins forming the human AMPK-TOR pathways across 412 species representing all three domains of life-prokaryotes (bacteria, archaea) and eukaryotes-and reconstructed their evolutionary history. The resulting phylogenetic profiles indicate the presence of primordial core pathways including seven proto-kinases in the last eukaryotic common ancestor. The evolutionary origins of the oldest components of the AMPK pathway, however, extend into the pre-eukaryotic era, and descendants of these ancient proteins can still be found in contemporary prokaryotes. The TOR complex in turn appears as a eukaryotic invention, possibly to aid in retrograde signaling between the mitochondria and the remainder of the cell. Within the eukaryotes, AMPK/TOR showed both a highly conserved core structure and a considerable plasticity. Most notably, KING1, a protein originally assigned as the γ subunit of AMPK in plants, is more closely related to the yeast SDS23 gene family than to the γ subunits in animals or fungi. This suggests its functional difference from a canonical AMPK γ subunit.