Which molecules inhibit the pyruvate dehydrogenase complex?

• A. High NADH and high acetyl-CoA inhibit PDH.
• B. High NAD+ and low acetyl-CoA inhibit PDH.
• C. Pyruvate inhibits PDH.
• D. CoA inhibits PDH.

Answer: (A)

Regulation of the pyruvate dehydrogenase complex hinges on the cell’s energy state, reflected by the NADH/NAD+ ratio and the level of acetyl-CoA. When NADH and acetyl-CoA are high, it signals that the cell already has plenty of energy and reducing equivalents, so PDH activity is dialed down. This happens because high NADH and acetyl-CoA promote the action of PDH kinase, which phosphorylates and inactivates the PDH complex. With PDH inhibited, the conversion of pyruvate to acetyl-CoA slows, preventing excess acetyl-CoA production.

In contrast, high NAD+ and low acetyl-CoA indicate low energy, which promotes PDH activation (via PDH phosphatase activity) and drives pyruvate processing toward acetyl-CoA production. Pyruvate itself is a substrate and, under low-energy conditions, acts to stimulate PDH rather than inhibit it. CoA by itself isn’t the primary inhibitory signal; the key inhibitor is acetyl-CoA, the product feedback signal.

So the correct statement reflects that high NADH and high acetyl-CoA inhibit the pyruvate dehydrogenase complex.