citrate shuttle
Summary
The citrate shuttle moves acetyl-CoA from the mitochondrial matrix to the cytosol as citrate, because acetyl-CoA itself cannot cross the inner membrane. Cytosolic ATP-citrate lyase regenerates acetyl-CoA for fatty acid synthesis, so the shuttle runs in the fed, high-energy state.
Detail
Meaning: Fatty acid synthesis occurs in the cytosol, but acetyl-CoA is made in the matrix (from pyruvate dehydrogenase and β-oxidation). When ATP and NADH are high, the citric acid cycle slows, citrate accumulates, and a transporter carries it out. In the cytosol, ATP-citrate lyase uses ATP and CoA to split citrate into acetyl-CoA and oxaloacetate. Oxaloacetate is reduced to malate by NADH. Malic enzyme then converts malate to pyruvate, CO₂ and NADPH, and pyruvate re-enters the matrix. The NADPH supports fatty acid synthesis; the pentose phosphate pathway is the other major NADPH source. Citrate in the cytosol also activates acetyl-CoA carboxylase, which makes malonyl-CoA in the committed step.
On the MCAT: Expect a lipogenesis passage asking where acetyl-CoA is made versus used, which enzyme releases it in the cytosol, or what happens if ATP-citrate lyase is inhibited (less cytosolic acetyl-CoA and less fatty acid synthesis). Conditions that raise ATP, such as a fed state with high insulin, favor citrate export.
Common confusion: Students mix it up with the carnitine shuttle, which brings fatty acyl groups into the matrix for β-oxidation (the opposite direction and purpose). It is also not the malate-aspartate shuttle, which moves NADH reducing equivalents. The citrate shuttle exports acetyl units for biosynthesis.
Sources
- Lehninger Principles of Biochemistry
- Biochemistry (Berg, Tymoczko, Stryer)
- Biochemistry (Voet and Voet)
Written for the MCAT and checked before it was published. For study reference only. Spotted an error? Let us know.