Control of mitochondrial metabolism by metabolic stress and hypoxia
Cell Biology
Final Report Abstract
In summary, our results support our hypothesis that hypoxia prevents an increase in mitochondrial activity by metabolic stressors such as AICAR, which simulates an increase in ADP and thus ATP demand. We were able to demonstrate that the stimulation of mitochondrial activity by AICAR depends on phosphorylation of AMPK and is dependent on the estrogen related receptor, ERRα, which acts as an enhancer loop for the PPAR/PGC1 induced increase in the expression of mitochondrial proteins. Hypoxia prevents this up-regulation, which might in part be due to a decrease in ERRα mRNA and protein in hypoxia, which should impair the function of the enhancer loop. We excluded a potential contribution of decreased activity of pyruvate dehydrogenase (PDH), which one would expect based on increased PDK-1 expression. Also autophagy seems not to play a role. Furthermore we were able to demonstrate that the inhibition of aerobic metabolism in hypoxia depends on the activation of HIF-1α, because it’s silencing prevented the hypoxia-induced decrease in basal oxygen consumption. Together these results indicate that there exists a variety of redundant mechanisms that all potentially decrease mitochondrial activity when cells become hypoxic, most of which depend on the activity of HIFs. The goal of this adjustment might be a decrease in the production of mitochondrial oxygen radicals that might cause irreversible cell damage. Because of reduced mitochondrial ATP production, hypoxia induces cell programming decreases the activity of energy consuming pathways such as protein synthesis and active ion transport (not studied in this setting).
