Figure 8. Proposed model of pyruvate cycle.

Tissue oxygen concentration decreases as the distance between cells and blood vessels increases. Cells in well-oxygenated areas mainly use ETC to regenerate NAD⁺; and a portion of pyruvate generated from glycolysis is released to the circulation, which may diffuse to hypoxic region. Hypoxic cells uptake exogenous pyruvate and use it as oxygen surrogate to maintain NAD⁺ availability, avoiding NAD⁺ depletion and eventual inhibition of glycolysis. In turn, the lactate released from hypoxic cells may be up-taken by the well-oxygenated cells and be oxidized to pyruvate.