RESPIRATORY AND METABOLIC ADAPTATION TO CELLULAR HYPOXIA

University Of Chicago, Chicago IL

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Abstract

DESCRIPTION (Applicant's abstract): Classical studies have shown that cellular respiration (VO2) remains independent of the O2 supply until the PO2 falls below a critical value (about 5 torr). Below that point, O2 supply limits VO2, ATP levels become depleted and ischemic injury ensues. Theoretically, cell survival during hypoxia might be enhanced if non-essential cell processes could be suspended, a response termed "hypoxic conformance of metabolism". Yet experimental evidence for such a response in mammalian cells during short periods of hypoxia has been lacking. Our studies reveal that cells from a wide range of tissues exhibit a 30-50 percent suppression in VO2 and ATP utilization rates when exposed to moderate hypoxia (PO2=10-50 torr) for longer periods, suggesting the participation of an intracellular signaling cascade. Hypoxic conformance is non-lethal, is fully reversible when the O2 tension is restored, and has significant functional consequences including decreased contractile function in cardiomyocytes and decreased acetaminophen metabolism in hepatocytes. Substantial preliminary data implicates mitochondrial cytochrome c oxidase as the "O2 sensor" in this response, by demonstrating that the catalytic function of the enzyme is modified during prolonged exposure to hypoxia. We hypothesize that this leads to a decrease in VO2, an increase in cellular (NADH), and a decline in mitochondrial transmembrane potential (psi). Specific Aim 1 will test the hypothesis that cytochrome oxidase function is modified at low PO2, and will identify the functional alterations in the enzyme underlying this response. Aim 2 will test the hypothesis that changes in mitochondrial psi participates in the coupling between the suppression of cytochrome oxidase function and the inhibition of ATP utilization during hypoxia. Aim 3 will test the hypothesis that facultative ATP-dependent cell functions are selectively inhibited, while reactions essential for cell homeostasis are preserved. Collectively, these studies are potentially significant for tissue injury in cardiopulmonary diseases involving limitations of O2 transport to tissues, and for patients with critical illnesses that may interfere with cellular O2 availability.