| The Krebs cycle metabolizes nutrients and generates electrons that feed the electron transport chain to drive production of ATP. The Krebs cycle also generates carbon dioxide (CO2), and as we previously demonstrated, the CO2/bicarbonate regulated soluble adenylyl cyclase (sAC) resides inside liver mitochondria, where it responds to this metabolically generated CO2 modulating the activity of complex IV (cytochrome c oxidase) of the electron chain. This CO2-sAC pathway thus links nutrient utilization with ATP generation. In this thesis, I demonstrate that this pathway is absent in mitochondria from sAC null mice, and although found in mitochondria from multiple tissues, it is not ubiquitous. In particular, the sAC-dependent CO2-sensing pathway seems to be absent from lung mitochondria.;How is metabolic homeostasis is achieved in species that do not contain sAC? Saccharomyces cerevisiae is an important model organism for metabolism and aging studies. This yeast contains a single adenylyl cyclase (CyrIp), which is homologous, but not closely related to sAC. Since cAMP signaling is known to play a central role in the glucose response and metabolism of yeast, I investigated whether Cyr1 p serves a role in yeast mitochondria analogous to mammalian mitochondrial sAC. In this thesis, I show that Cyrip localizes to mitochondria and serves a functional role in oxidative phosphorylation (OXPHOS). Therefore, it appears that the mitochondrially localized adenlylyl cyclase pathway originally discovered in liver is widely, but not ubiquitously, distributed in mammals, and is evolutionarily conserved among eukaryotes. |
