Figure 236

Schematic diagram illustrating how mitochondria generate energy. The diagram indicates the ATP synthase complex and the electron transport chain of proteins located in the inner mitochondrial membrane. The electron transport chain generates a proton gradient between the matrix and intermembrane space that is used to produce ATP. Numbers represent sequential proteins involved in the electron transport chain and ATP production: 7, NADH dehydrogenase complex; 2, ubiquinone; 3, cytochrome b-c, complex; 4, cytochrome c; 5, cytochrome oxidase complex; and 6, ATP synthase complex.

electron-transport chain of respiratory enzymes (see Fig. 2.36). The transfer of H1 across the inner mitochondrial membrane establishes an electrochemical proton gradient. This gradient creates a large proton motive force that causes the movement of H' down its electrochemical gradient through a large, membrane-bound enzyme called ATP synthase. ATP synthase provides a pathway across the inner mitochondrial membrane in which H+ ions are used to drive the energetically unfavorable reactions leading to synthesis of ATP. This movement of protons back to the mitochondrial matrix is referred to as chemiosmotic coupling. The newly produced ATP is transported from the matrix to the intermembrane space by the voltage gradient-driven ATP/ADP exchange protein located in the inner mitochondrial membrane. From here, ATP leaves the mitochondria via voltage-dependent anion channels in the outer membrane to enter the cytoplasm. At the same time, ADP produced in the cytoplasm rapidly enters the mitochondria for recharging.

Mitochondria undergo morphologic changes related to their functional state

TEM studies show mitochondria in two distinct configurations. In the orthodox configuration, the cristae are prominent and the matrix compartment occupies a large part of the total mitochondrial volume. This configuration corresponds to a low level of oxidative phosphorylation. In the condensed configuration, cristae are not easily recognized, the matrix is concentrated and reduced in volume, and the intermembrane space increases to as much as 50% of the total volume. This configuration corresponds to a high level of oxidative phosphorylation.

Mitochondria decide if the cell lives or dies

Recent experimental studies indicate that mitochondria sense cellular stress and are capable of deciding whether the cell lives or dies by initiating apoptosis (programmed cell death). The major cell death event generated by the mitochondria is the release of cytochrome c from the mitochondrial intermembranous space into the cell cytoplasm. This event, regulated by the Bcl-2 protein family (see page 74), initiates the cascade of proteolytic enzymatic reactions that leads to apoptosis.

Peroxisomes (Microbodies)

Peroxisomes are single membrane-bounded organelles containing oxidative enzymes

Peroxisomes (microbodies) are small (0.5 ¡xm diameter), membrane-limited spherical organelles that contain oxidative enzymes, particularly catalase and other peroxidases. Virtually all oxidative enzymes produce hydrogen peroxide (H202) as a product of the oxidation reaction. Hydrogen peroxide is a toxic substance. The catalase universally present in peroxisomes carefully regulates the cellular hydrogen peroxide content by breaking down hydrogen peroxide, thus protecting the cell. In addition, peroxisomes contain D-amino acid oxidases, /3-oxidation enzymes, and numerous other enzymes.

Oxidative enzymes are particularly important in liver cells (hepatocytes), where they perform a variety of detoxification processes. Peroxisomes in hepatocytes are responsible for detoxification of ingested alcohol by converting it to acetaldehyde. /3-Oxidation of fatty acids is also a major function of peroxisomes. In some cells, peroxisomal fatty acid oxidation may equal that of mitochondria. The proteins contained in the peroxisome lumen and membrane are synthesized on cytoplasmic ribosomes and imported into the peroxisome. A protein destined for peroxisomes must have a peroxisomal targeting signal attached to its C-terminus.

Although abundant in liver and kidney cells, peroxisomes are found in most other cells. The number of peroxisomes present in a cell increases in response to diet, drugs, and hormonal stimulation. In most animals, but not humans, peroxisomes also contain urate oxidase (uricase), which often appears as a characteristic crystalloid inclusion ('nucleoid,).

Various human metabolic disorders are caused by the inability to import peroxisomal proteins into the organelle because of faulty peroxisomal targeting signal. Several severe disorders are associated with nonfunctional peroxisomes. In the most common inherited disease related to nonfunctional peroxisomes, Zelliveger syndrome, which leads to early death, peroxisomes lose their ability to function because of lack of necessary enzymes. Therapies for peroxisomal disorders have been unsatisfactory to date.

V NONMEMBRANOUS ORGANELLES Microtubules

Microtubules are nonbranching and rigid hollow tubes of protein that can rapidly disassemble in one location and reassemble in another. In general, they grow from the microtubule-organizing center (MTOC) located near the nucleus (page 53) and extend toward the cell periphery. Microtubules create a system of connections within the cell, frequently compared to railroad tracks, along which vesicular movement occurs.

Microtubules are elongated polymeric structures composed of equal parts of «-tubulin and /Mubulin

Microtubules measure 20 to 25 nm in diameter (Fig. 2.37). The wall of the microtubule is approximately 5 nm thick and consists of 13 circularly arrayed globular dimeric tubulin molecules. The tubulin dimer has a molecular weight of 110 kDa and is formed from an «-tubulin and a /3-tubu-lin molecule, each with a molecular weight of 55 kDa. (Fig.

Electron micrographs of microtubules, a. Micrograph showing microtubules (arrows) of the mitotic spindle in a dividing cell. On the right, the microtubules are attached to chromosomes. x30,000. b. Micrograph of microtubules (arrows) in the axon of a nerve cell. In both cells, the microtubules are seen in longitudinal profile. x30,000.

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