Mitochondrial Respiration Is Controlled by Key Metabolites

The substrates of ATP synthesis—ADP and P;—appear to be key regulators of the rates of glycolysis in the cytosol, as well as the citric acid cycle and oxidative phosphorylation in the mitochondria. Control points exist at all three stages of respiration; here we will give just a brief overview of some major features.

The best-characterized site of regulation of the citric acid cycle is at the pyruvate dehydrogenase complex, which is reversibly phosphorylated by a regulatory kinase and a phos-

CADP)

PDH KP)

PDH kinase

<ATp

PDH KP)

PDH kinase

<ATp

phosphatase

phosphatase

Effect on PDH activity

Pyruvate ADP

Mg2+ (or Mn2+)

Inhibits kinase Inhibits kinase Stimulates phosphatase

Inactivating NADH

Inhibits PDH Stimulates kinase

Acetyl CoA

Inhibits PDH Stimulates kinase

nh4+

Inhibits PDH Stimulates kinase

FIGURE 11.11 Regulation of pyruvate dehydrogenase (PDH) activity by reversible phosphorylation and by other metabolites.

FIGURE 11.11 Regulation of pyruvate dehydrogenase (PDH) activity by reversible phosphorylation and by other metabolites.

phatase. Pyruvate dehydrogenase is inactive in the phos-phorylated state, and the regulatory kinase is inhibited by pyruvate, allowing the enzyme to be active when substrate is available (Figure 11.11). In addition, several citric acid cycle enzymes, including pyruvate dehydrogenase and 2-oxoglu-tarate dehydrogenase, are directly inhibited by NADH.

Fructose-6-phosphate

r \

Fructose-1,6-bisphosphate

FIGURE 11.12 Concept of bottom-up regulation of plant respiration. Several substrates for respiration (e.g., ADP) stimulate enzymes in early steps of the pathways (green arrows . In contrast, accumulation of products (e.g., ATP) inhibits (red squares) earlier reactions in a stepwise fashion. For instance, ATP inhibits the electron transport chain leading to an accumulation of NADH. NADH inhibits citric acid enzymes such as isocitrate dehydrogenase and 2-oxoglu-tarate dehydrogenase. Then, citric acid cycle intermediates like citrate inhibit the PEP-metabolizing enzymes in the cytosol. Finally, PEP inhibits the conversion of fructoses-phosphate to fructose-1,6-biphosphate and restricts carbon feeding into glycolysis.

FIGURE 11.12 Concept of bottom-up regulation of plant respiration. Several substrates for respiration (e.g., ADP) stimulate enzymes in early steps of the pathways (green arrows . In contrast, accumulation of products (e.g., ATP) inhibits (red squares) earlier reactions in a stepwise fashion. For instance, ATP inhibits the electron transport chain leading to an accumulation of NADH. NADH inhibits citric acid enzymes such as isocitrate dehydrogenase and 2-oxoglu-tarate dehydrogenase. Then, citric acid cycle intermediates like citrate inhibit the PEP-metabolizing enzymes in the cytosol. Finally, PEP inhibits the conversion of fructoses-phosphate to fructose-1,6-biphosphate and restricts carbon feeding into glycolysis.

The citric acid cycle oxidations, and subsequently respiration, are dynamically controlled by the cellular level of adenine nucleotides. As the cell's demand for ATP in the cytosol decreases relative to the rate of synthesis of ATP in the mitochondria, less ADP will be available, and the electron transport chain will operate at a reduced rate (see Figure 11.10). This slowdown could be signaled to citric acid cycle enzymes through an increase in matrix NADH, inhibiting the activity of several citric acid cycle dehydro-genases (Oliver and McIntosh 1995).

The buildup of citric acid cycle intermediates and their derivates, such as citrate and glutamate, inhibits the action of cytosolic pyruvate kinase, increasing the cytosolic PEP concentration, which in turn reduces the rate of conversion of fructose-6-phosphate to fructose-1,6-bisphosphate, thus inhibiting glycolysis.

In summary, plant respiratory rates are controlled from the "bottom up" by the cellular level of ADP (Figure 11.12). ADP initially regulates the rate of electron transfer and ATP synthesis, which in turn regulates citric acid cycle activity, which, finally, regulates the rate of the glycolytic reactions.

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