The Glycerophosphate Shuttle Ensures Efficient Use of Cytosolic NADH

In the glycerophosphate shuttle, two different glycerophosphate dehydrogenases, one in the cytosol
and one on the outer face of the mitochondrial inner
membrane, work together to carry electrons into the mitochondrial matrix (see
Figure 20.31). NADH produced in the cytosol transfers its electrons to
dihydroxyacetone phosphate, thus reducing it to glycerol-3-phosphate. This
metabolite is reoxidized by the FAD-dependent mitochondrial membrane enzyme to reform
dihydroxyacetone phosphate and enzyme-bound FADH2. The
two electrons of [FADH2] are passed directly to UQ, forming UQH2. Thus, via
this shuttle, cytosolic NADH can be used to produce mitochondrial [FADH2]
and, subsequently, UQH2. As a result, cytosolic NADH oxidized via this shuttle
route yields only 1.5 molecules of ATP. The cell “pays” with a potential ATP molecule for the convenience
of getting cytosolic NADH into the mitochondria. Although this may seem wasteful, there is an important
payoff. The glycerophosphate shuttle is essentially irreversible, and even when NADH levels are very low
relative to NAD, the cycle operates effectively.
The Malate–Aspartate Shuttle Is Reversible
The second electron shuttle system, called the malate–aspartate shuttle, is shown
in Figure 20.32. Oxaloacetate is reduced in the cytosol, acquiring the electrons of
NADH (which is oxidized to NAD). Malate is transported across the inner membrane, where it is
reoxidized by malate dehydrogenase, converting NAD to NADH
in the matrix. This mitochondrial NADH readily enters the electron-transport
chain. The oxaloacetate produced in this reaction cannot cross the inner membrane and must be
transaminated to form aspartate, which can be transported
across the membrane to the cytosolic side. Transamination in the cytosol recycles
aspartate back to oxaloacetate. In contrast to the glycerol phosphate shuttle, the
malate–aspartate cycle is reversible, and it operates as shown in Figure 20.32 only
if the NADH/NAD ratio in the cytosol is higher than the ratio in the matrix. Because this shuttle produces
NADH in the matrix, the full 2.5 ATPs per NADH are
recovered.