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. Author manuscript; available in PMC: 2012 Oct 5.

Published in final edited form as: Cell Metab. 2011 Oct 5;14(4):443–451. doi: 10.1016/j.cmet.2011.07.014

In conditions of low glucose uptake and flux through glycolysis (left), the glucose flux that passes through glycolysis and generates NADH is balanced by a mitochondrial shuttling mechanism. In conditions of high glucose uptake and flux (right), the capacity of the malate-aspartate shuttle to regenerate NAD⁺ can be saturated and lactate dehydrogenase activity is required to regenerate NAD⁺. A proposition is that this behavior can explain the Warburg effect. The thickness of the arrows represents relative magnitudes of flux at different points in the glycolytic pathway. (inset) The malate-aspartate shuttle: a series of oxidation-reduction reactions and anti-porter based trafficking of intermediate metabolites that begins with the oxidation of malate and end with reduction of aspartate in a series of six reactions. Directed arrows denote the conversion of substrate to product. The net result is a regeneration of NAD⁺ in the cytosol and production of NADH in the mitochondria. Abbreviations: MAL – malate, ASP – aspartate, αKG – alpha-ketoglutarate, OAA – oxaloacetate, and GLU – glutamate.

In conditions of low glucose uptake and flux through glycolysis (left), the glucose flux that passes through glycolysis and generates NADH is balanced by a mitochondrial shuttling mechanism. In conditions of high glucose uptake and flux (right), the capacity of the malate-aspartate shuttle to regenerate NAD⁺ can be saturated and lactate dehydrogenase activity is required to regenerate NAD⁺. A proposition is that this behavior can explain the Warburg effect. The thickness of the arrows represents relative magnitudes of flux at different points in the glycolytic pathway. (inset) The malate-aspartate shuttle: a series of oxidation-reduction reactions and anti-porter based trafficking of intermediate metabolites that begins with the oxidation of malate and end with reduction of aspartate in a series of six reactions. Directed arrows denote the conversion of substrate to product. The net result is a regeneration of NAD⁺ in the cytosol and production of NADH in the mitochondria. Abbreviations: MAL – malate, ASP – aspartate, αKG – alpha-ketoglutarate, OAA – oxaloacetate, and GLU – glutamate.