Medini, H.; Mishmar, D.

Interactions between mitochondrial and nuclear factors are essential to life. Nevertheless, the importance of coordinated regulation of mitochondrial-nuclear gene expression (CMNGE) to changing physiological conditions is poorly understood, and is limited to certain tissues and certain organisms. We hypothesized that CMNGE is important for development across vertebrates, and hence will be conserved. As a first step, we analyzed >1400 RNA-seq experiments performed during embryo development, neonates and adults across vertebrate evolution. We found conserved sharp elevation after birth of CMNGE, including oxidative phosphorylation (OXPHOS) and mitochondrial ribosome genes, in heart, hindbrain, forebrain and kidney across mammals, Gallus gallus and in the lizard Anolis carolinensis. This was accompanied by elevated expression of TCA cycle enzymes, and reduction in hypoxia response genes, suggesting a conserved cross-tissue metabolic switch after birth/hatching. Analysis of ~70 known regulators of mitochondrial gene expression revealed consistently elevated expression of PGC-1a and C/EBPB after birth/hatching across organisms and tissues, thus highlighting them as candidate regulators of CMNGE upon transition to the neonate. Analyses of Danio rerio, Xenopus tropicalis and Drosophila melanogaster revealed elevated CMNGE prior to hatching, coinciding with the development of motor neurons. Lack of such ancient pattern in mammals and in the chicken suggests that it was lost during radiation of terrestrial vertebrates. Taken together, our results suggest that regulated CMNGE during embryogenesis and after birth, alludes to metabolic switch which is under strong selective constraints and hence essential.