Evolution of the PGC-1 protein family in the control of oxidative metabolism in vertebrates
Le Moine, Christophe Marie Renaud
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Mitochondrial biogenesis requires an intricate transcriptional coordination between the nuclear and mitochondrial genomes to establish the structural and functional components of the organelle. This coordination is paramount in vertebrate muscles where oxidative capacity must be adjusted to meet varying energy demands. I investigated the regulatory circuits controlling mitochondrial content in vertebrate muscle in the context of development, adaptation to nutritional status and temperature, and in an evolutionary perspective. Initial experiments focused on the role of transcriptional regulators in the metabolic changes in the myocardium of aging rat. I hypothesized that the changes in oxidative capacity associated with aging would be primarily driven by the peroxisome proliferator activated-receptors (PPARs), the nuclear respiratory factors (NRFs) and their common coactivator PPARgamma coactivator-1alpha (PGC-1alpha). However, the reduction in oxidative capacity in the heart of old rats was independent of these regulatory axes and occurred partially through post-transcriptional processes. The next series of experiments investigated the transcriptional networks regulating the metabolic remodelling in goldfish subjected to dietary and temperature stress. As a potent regulator of mitochondrial proliferation in mammals, I hypothesized that PGC-1alpha assumed a similar role in lower vertebrates. Similar to their mammalian homologues, PPARalpha and NRF-1 assumed their respective roles in regulating lipid metabolism and mitochondrial proliferation in goldfish. In contrast, PGC-1alpha was only a good predictor of the PPAR axis, while PGC-1beta was a better indicator of the NRF-1 and mitochondrial gene expression axis. This apparent divergence of the PGC-1alpha homologues in vertebrates inspired the subsequent study, in which I investigated the evolutionary history of the PGC-1 family in vertebrates. Specifically, I sought to assess if PGC-1alpha functional divergence had a structural and evolutionary basis. PGC-1alpha phylogeny revealed asymmetric rates of evolution across the different domains of the protein. The domains essential to PGC-1alpha coactivating activity as well as PPARs interaction motifs were relatively well preserved in all lineages. In contrast, the NRF-1 interacting domain experienced accelerated rates of evolution in fish lineages compared to tetrapods. In addition, fish PGC-1alpha exhibited consequent insertions in this domain that could have important repercussions on its ability to bind NRF-1 and regulate mitochondrial gene expression.