In addition to ATP, biosynthesis in the cytosol requires both a constant supply of reducing power in the form of NADPH and small carbon-rich molecules to serve as building blocks (discussed in Chapter 2). Descriptions of biosynthesis often state that the needed carbon skeletons come directly from the breakdown of sugars, whereas the NADPH is produced in the cytosol by a side pathway for the breakdown of sugars (the pentose phosphate pathway, an alternative to glycolysis). But under conditions where nutrients abound and plenty of ATP is available, mitochondria help to generate both the reducing power and the carbon-rich building blocks (the “carbon skeletons” in Panel 2–1, pp. 90–91) needed for cell growth. For this purpose, excess citrate produced in the mitochondrial matrix by the citric acid cycle (see Panel 2–9, pp. 106–107) is transported down its electrochemical gradient to the cytosol, where it is metabolized to produce essential components of the cell. Thus, for example, as part of a cell’s response to growth signals, large amounts of acetyl CoA are produced in the cytosol from citrate exported from mitochondria, accelerating the production of the fatty acids and sterols that build new membranes (described in Chapter 10). Cancer cells are frequently mutated in ways that enhance this pathway, as part of their program of abnormal growth (see Figure 20–26).
The urea cycle is a central metabolic pathway in mammals that converts the ammonia (NH4+) produced by the breakdown of nitrogen-containing compounds (such as amino acids) to the urea excreted in urine. Two critical steps of the urea cycle are carried out in the mitochondria of liver cells, while the remaining steps occur in the cytosol. Mitochondria also play an essential part in the metabolic adaptation of cells to different nutritional conditions. For example, under conditions of starvation, proteins in our bodies are broken down to amino acids, and the amino acids are imported into mitochondria and oxidized to produce NADH for ATP production.
The biosynthesis of heme groups—which, as we shall see in the next section, play a central part in electron transfer—is another critical process that is shared between the mitochondrion and the cytoplasm. Iron–sulfur clusters, which are essential not only for electron transfer in the respiratory chain (see p. 766), but also for the maintenance and stability of the nuclear genome, are produced in mitochondria (and chloroplasts). Nuclear genome instability, a hallmark of cancer, can sometimes be linked to the decreased function of cellular proteins that contain iron–sulfur clusters.
Mitochondria also have a central role in membrane biosynthesis. Cardiolipin is a two-headed phospholipid (Figure 14–11) that is confined to the inner mitochondrial membrane, where it is also produced. But mitochondria are also a major source of phospholipids for the biogenesis of other cell membranes. Phosphatidylethanolamine, phosphatidylglycerol, and phosphatidic acid are synthesized in the mitochondrion, while phosphatidylinositol, phosphatidylcholine, and phosphatidylserine are primarily synthesized in the endoplasmic reticulum (ER). As described in Chapter 12, most of the cell’s membranes are assembled in the ER. The exchange of lipids between the ER and mitochondria is thought to occur at special sites of close contact (see Figure 14–7) by an as-yet unknown mechanism.