In this review we focus on the mechanisms underlying the coordinated regulation of metabolic demand and supply during hypoxia resulting in metabolic adaptation to maintain cellular homeostasis
2010
Key concepts
Scholarcy highlights
- Adaptation to lowering oxygen levels requires coordinated downregulation of metabolic demand and supply to prevent a mismatch in ATP utilization and production that might culminate in a bioenergetic collapse
- Previous studies failed to observe a decrease in the respiratory rate during hypoxia because isolated cells were exposed to hypoxia for seconds
- In this review we focus on the mechanisms underlying the coordinated regulation of metabolic demand and supply during hypoxia resulting in metabolic adaptation to maintain cellular homeostasis
- The electrons generated from NADH and FADH2 undergo oxidation to NAD+ and FAD+ by complex I and II of the electron transport chain located in the inner mitochondrial membrane
- In the ensuing decades it has become clear that other factors control the respiratory rate, such as the availability of reducing equivalents provided by the tricarboxylic acid cycle, electron flux through the ETC, the availability of ADP provided by cellular ATPases, the adenine nucleotide translocase, and the magnitude of the proton leak
- The same low levels of nitric oxide are sufficient to inhibit respiration and initiate cell death under hypoxia
- In the late 1980s, Brand and colleagues began to utilize metabolic control analysis on isolated rat hepatocytes exposed to ambient air and determined that 15–30% of respiration is controlled by the NADH supply; 20% is controlled by the proton leak; and 0–15% is controlled by the ETC
- This coordinated downregulation of demand and supply prevents a mismatch in ATP production and utilization that might culminate in bioenergetic collapse while limiting the production of ROS and slowing the rate of oxygen depletion under ischemic conditions
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