When the O2 supply from blood fails to meet the demand of O2 -consuming cells, oxygen deprivation (hypoxia) occurs. This is common, for example, in exercising muscle. It has been recognized for over 100 years that O2 -deprived cells show increased conversion of glucose to lactate, known as the Pasteur Effect. Activation of the Pasteur Effect during hypoxia is mediated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is a transcription factors that upregulates the expression of several glycolytic enzymes that support the increased glycolytic ATP production as mitochondria become starved for O2. At the same time glycolysis is increasing, the rate of mitochondrial respiration decreases. New research reveals that in addition to upregulating enzymes in the glycolytic pathway, HIF-1 also induces the expression of cytoplasmic lactate dehydrogenase (LDH) and mitochondrial pyruvate dehydrogenase kinase (PDK).
(a) Explain why glucose consumption must increase in hypoxic tissues to provide the same amount of ATP that could be produced from glucose in normoxic (normal O2 levels) tissues.
(b) How would increasing LDH expression increase the rate of glycolysis?
(c) How would increasing PDK expression decrease the rate of mitochondrial respiration?