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Mitochondria evolved from ancestral prokaryotes that were engulfed by primitive eukaryotes about 1.5 billion years ago. Their origin explains why mitochondria contain their own DNA genome (circularized, about 1% of the total cellular DNA), which encodes roughly 1% of the total cel- lular proteins and approximately 20% of the proteins involved in oxidative phosphorylation. Although their genomes are small, mitochondria can nevertheless perform all the steps of DNA replication, transcription, and transla- tion. Interestingly, the mitochondrial machinery is similar to present-day bacteria; for example, mitochondria initiate protein synthesis with N-formylmethionine and are sensi- tive to anti-bacterial antibiotics. #180 в контекст | | |
Mitochondria are dynamic, constantly undergoing fission and fusion with other mitochondria; in this way, mitochondria can undergo regular renewal to stave off degenerative changes that might occur because of genetic disorders or oxygen free radical damage. Mitochondria turn over rapidly, with estimated half-lives ranging from 1 to 10 days, depending on the tissue, nutritional status, meta- bolic demands, and intercurrent injury. Because the ovum #181 в контекст | | |
contributes the vast majority of cytoplasmic organelles to the fertilized zygote, mitochondrial DNA is virtually entirely maternally inherited. However, because the protein constituents of mitochondria derive from both nuclear and mitochondrial genetic transcription, mitochondrial disor- ders may be X-linked, autosomal, or maternally inherited. Mitochondria provide the enzymatic machinery for oxi- dative phosphorylation (and thus the relatively efficient generation of energy from glucose and fatty acid sub- strates). They also have central roles in anabolic metabo- lism and the regulation programmed cell death, so-called “apoptosis” (Fig. 1.11). #182 в контекст | | |
Energy Generation. Each mitochondrion has two sepa- rate and specialized membranes. The inner membrane con- tains the enzymes of the respiratory chain folded into cristae. This encloses a core matrix space that harbors the bulk of certain metabolic enzymes, such as the enzymes of the citric acid cycle. Outside the inner membrane is the intermembrane space, site of ATP synthesis, which is, in turn, enclosed by the outer membrane; the latter is studded with porin proteins that form aqueous channels permeable to small (<5000 daltons) molecules. Larger mol- ecules (and even some smaller polar species) require spe- cific transporters. #183 в контекст | | |
The major source of the energy needed to run all basic cellular functions derives from oxidative metabolism. Mitochondria oxidize substrates to CO2, and in the process transfer high-energy electrons from the original molecule (e.g., gluocse) to molecular oxygen to water. The oxidation of various metabolites drives hydrogen ion (proton) pumps that transfer H+ ions from the core matrix into the inter- membrane space. As these H+ ions flow back down their electrochemical gradient, the energy released is used to synthesize ATP. #184 в контекст | | |
It should be noted that the electron transport chain need not necessarily be coupled to ATP generation. Thus, an inner membrane protein enriched in brown fat called ther- mogenin (or UCP-1 = uncoupling protein 1) is a proton #185 в контекст | | |
transporter that can dissipate the proton gradient (uncou- ple it from oxidative phosphorylation) in the form of heat (nonshivering thermogenesis). As a natural (albeit usually low-level) byproduct of substrate oxidation and electron transport, mitochondria also are an important source of reactive oxygen species (e.g., oxygen free radicals, hydro- gen peroxide); importantly, hypoxia, toxic injury, or even mitochondrial aging can lead to significantly increased levels of intracellular oxidative stress. #186 в контекст | | |
Intermediate Metabolism. Pure oxidative phosphoryla- tion produces abundant ATP, but also “burns” glucose to CO2 and H2O, leaving no carbon moieties for use as build- ing blocks for lipids or proteins. For this reason, rapidly growing cells (both benign and malignant) increase glucose and glutamine uptake and decrease their production of ATP per glucose molecule—forming lactic acid in the pres- ence of adequate oxygen—a phenomenon called the Warburg effect (or aerobic glycolysis). Both glucose and glutamine provide carbon moieties that prime the mito- chondrial tricarboxylic acid (TCA) cycle, but instead of being used to make ATP, intermediates are “spun off” to make lipids, nucleic acids, and proteins. Thus, depending on the growth state of the cell, mitochondrial metabolism can be modulated to support either cellular maintenance or cellular growth. Ultimately, growth factors, nutrient supplies, and oxygen availability, as well as cellular signal- ing pathways and sensors that respond to these exogenous factors, govern these metabolic decisions. #187 в контекст | | |
Cell Death. Mitochondria are like the proverbial Dr. Jekyll and Mr. Hyde. On the one hand, they are factories of energy production in the form of ATP that allow the cells to survive; on the other hand, they participate in driving cell death when the cells are exposed to noxious stimuli #188 в контекст | | |
that the cells cannot adapt to. The role of mitochondria in the two principle forms of cell death, necrosis and apopto- sis, are discussed in Chapter 2. In addition to providing ATP and metabolites that enable the bulk of cellular activ- ity, mitochondria also regulate the balance of cell survival and death. #189 в контекст | | |
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Cell communication is critical in multicellular organisms. At the most basic level, extracellular signals determine whether a cell lives or dies, whether it remains quiescent, or whether it is stimulated to perform a specific function. Intercellular signaling is important in the developing embryo, in maintaining tissue organization, and in ensur- ing that tissues respond in an adaptive and effective fashion to various threats, such as local tissue trauma or a systemic infection. Loss of cellular communication and the “social controls” that maintain normal relationships of cells can variously lead to unregulated growth (cancer) or an inef- fective response to an extrinsic stress (as in shock). #191 в контекст | | |
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An individual cell is constantly exposed to a remarkable cacophony of signals, which must be “interpeted” and inte- grated into responses that benefit the organism as a whole. Some signals may induce a given cell type to differentiate, others may stimulate proliferation, and yet others may direct the cell to perform a specialized function. Multiple signals received in combination may trigger yet another totally unique response. Many cells require certain inputs just to continue living; in the absence of appropriate exog- enous signals, they die by apoptosis. #193 в контекст | | |
The sources of the signals that most cells respond to can be classified into several groups: #194 в контекст | | |
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Pathogens and damage to neighboring cells. Many cells have an innate capacity to sense and respond to damaged cells (danger signals), as well as foreign invaders such as microbes. The receptors that generate these danger signals are discussed in Chapters 3 and 5. #196 в контекст | | |
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Cell-cell contacts, mediated through adhesion molecules and/or gap junctions. As mentioned previously, gap junction signaling is accomplished between adjacent cells via hydrophilic connexons that permit the movement of small ions (e.g., calcium), various metabolites, and potential second messenger molecules such as cAMP. #198 в контекст | | |
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Cell-ECM contacts, mediated through integrins, which are discussed in Chapter 3 in the context of leukocyte attachment to other cells during inflammation. #200 в контекст | | |
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Secreted molecules. The most important secreted mol- ecules include growth factors, discussed later; cytokines, a term reserved for mediators of inflammation and immune responses (also discussed in Chapters 3 and 5); and hormones, which are secreted by endocrine organs and act on different cell types (Chapter 20). #202 в контекст | | |
Signaling pathways also can be classified into different types based on the spatial relationships between the sending and receiving cells: #203 в контекст | | |
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Paracrine signaling. Cells in just the immediate vicinity are affected. Paracrine signaling may involve trans- membrane “sending” molecules that activate receptors on adjacent cells or secreted factors that diffuse for only short distances. In some instances, the latter is achieved by having secreted factors bind tightly to ECM. #205 в контекст | | |
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Autocrine signaling occurs when molecules secreted by a cell affect that same cell. This can serve as a means to entrain groups of cells undergoing synchronous differ- entiation during development, or it can be used to amplify (positive feedback) or dampen (negative feed- back) a response. #207 в контекст | | |
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Synaptic signaling. Activated neurons secrete neurotrans- mitters at specialized cell junctions (synapses) onto target cells. #209 в контекст | | |
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Endocrine signaling. A hormone is released into the bloodstream and acts on target cells at a distance. #211 в контекст | | |
Regardless of the nature of an extracellular stimulus (paracrine, synaptic, or endocrine), the signal it conveys is transmitted to the cell via a specific receptor protein. Signaling molecules (ligands) bind their respective recep- tors and initiate a cascade of intracellular events culminat- ing in the desired cellular response. Ligands usually have high affinities for receptors and at physiologic concentra- tions bind receptors with exquisite specificity. Receptors may be present on the cell surface or located within the cell (Fig. 1.12): #212 в контекст | | |
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Intracellular receptors include transcription factors that are activated by lipid-soluble ligands that easily transit plasma membranes. Examples include vitamin D and steroid hormones, which activate nuclear hormone receptors. In other settings, a small and/or nonpolar signaling ligand can diffuse into adjacent cells. Such is the case for nitric oxide (NO), through which endothe- lial cells regulate intravascular pressure. NO is gener- ated by an activated endothelial cell and then diffuses into adjacent vascular smooth muscle cells; there it activates guanylyl cyclase to generate cyclic GMP, an intracellular second signal that causes smooth muscle relaxation. #214 в контекст | | |
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Cell-surface receptors are generally transmembrane pro- teins with extracellular domains that bind activating ligands. Depending on the receptor, ligand binding may #216 в контекст | | |
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electrically excitable cells), (2) activate an associated GTP-binding regulatory protein (G protein), (3) activate an endogenous or associated enzyme, often a tyrosine kinase, or (4) trigger a proteolytic event or a change in protein binding or stability that activates a latent tran- scription factor. Activities (2) and (3) are associated with growth factor signaling pathways that drive cell prolif- eration, whereas activity (4) is a common feature of mul- tiple pathways (e.g., Notch, Wnt, and Hedgehog) that regulate normal development. Understandably, signals transduced by cell surface receptors are often deranged in developmental disorders and in cancers. #219 в контекст | | |
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Binding of a ligand to a cell surface receptor mediates sig- naling by inducing clustering of the receptor (receptor crosslinking) or other conformational changes (Fig. 1.12). #221 в контекст | | |
The common theme is that all of these perturbations cause a change in the physical state of the intracellular domain of the receptor, which then triggers additional biochemical events that lead to signal transduction. #222 в контекст | | |
Cellular receptors are grouped into several types based on the signaling mechanisms they use and the intracel- lular biochemical pathways they activate (Fig. 1.12). Receptor signaling most commonly leads to the formation or modification of biochemical intermediates and/or acti- vation of enzymes, and ultimately to the generation of active transcription factors that enter the nucleus and alter gene expression: #223 в контекст | | |
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Receptors associated with kinase activity. Downstream phosphorylation is a common pathway of signal trans- duction. Changes in receptor geometry can stimulate intrinsic receptor protein kinase activity or promote the enzymatic activity of recruited intracellular kinases. These kinases add charged phosphate residues to target molecules. Tyrosine kinases phosphorylate spe- cific tyrosine residues, whereas serine/threonine kinases add phosphates to distinct serine or threonine residues, and lipid kinases phosphorylate lipid substrates. For every phosphorylation event, there is also a potential counter-regulatory phosphatase, an enzyme that can remove the phosphate residue and thus modulate sig- naling; usually, phosphatases play an inhibitory role in signal transduction. #225 в контекст | | |
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Receptor tyrosine kinases (RTKs) are integral membrane proteins (e.g., receptors for insulin, epidermal growth factor, and platelet-derived growth factor [PDGF]); ligand-induced crosslinking activates intrinsic tyrosine kinase domains located in their cytoplasmic tails. #227 в контекст | | |
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