Hypoxia: A succinate-fumarate electron shuttle between peripheral cells and lung

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Abstract
The objective of this investigation was to determine if the succinate that accumulates in anoxic or hypoxic tissues of mammals is (a) increased in concentration in the blood, (b) excreted in the urine or (c) recycled in some manner. Rats were subjected to 0.4 atm and the plasma analyzed for succinate and fumarate at 2 hours, 24 hours and 28 days. Significant increases of succinate or succinate plus fumarate were obtained at 2 hours and at 28 days at 0.4 atm. Analysis of 24-hour samples of urine obtained from controls and animals at 0.4 atm for 28 days demonstrated that no substantial increase in succinate excretion occurred with acclimation. Lung slices were incubated in Krebs-Ringer bicarbonate and succinate and gassed with O2:CO2 (95:5). Such oxygenated lung slices not only utilized succinate but produced a comparable quantity of fumarate plus malate. It is concluded that succinate produced from fumarate and α-ketoglutarate in peripheral hypoxic tissue is transported by the blood to the oxygenated lungs. There it is oxidized to fumarate and recycled as fumarate and malate to the periphery. In this way metabolites can act as electron shuttles between peripheral cells and lung.