The effects of glucagon stimulation on phosphorylation of hepatic mitochondrial proteome

The liver is an essential metabolic organ that maintains normal blood glucose levels by balancing between glucose storage and mobilization, controlled primarily by the counteracting effects of insulin and glucagon. Specifically, glucagon promotes hepatic gluconeogenesis and glycogenolysis to maintain homeostatic blood glucose concentrations in the post-absorptive state. Hepatocyte mitochondria play an essential role in metabolism during fasting. They provide the energy required to support gluconeogenesis by enhancing the TCA cycle and oxidative phosphorylation rates and by oxidizing fatty acids to generate ATP. In addition, they perform the initial reactions essential for channeling substrates into gluconeogenesis.

While it is well-accepted that glucagon significantly modulates mitochondrial processes, partially through control of intracellular and mitochondrial calcium levels, our understanding of how glucagon regulates mitochondria function is far from being complete. Elucidating the mechanisms by which glucagon controls mitochondrial adaptations to changing metabolic demands and the pathogenic alterations that underlie metabolic disorders represent principal challenges in cell biology. We hypothesize that regulation of liver metabolism during fasting, by glucagon, is partially controlled by altered phosphorylation of mitochondrial proteins. Here, we present phosphoproteome analysis of mitochondria isolated from liver tissue following glucagon administration. Our preliminary data highlights the importance of glucagon in acutely regulating multiple mitochondrial processes pertinent to the metabolic adaptation of the liver to fasting.