Mitochondria Krebs cycle

Oxidizible substrates from glycolysis, fatty acid or protein catabolism enter the mitochondrion in the form of acetyl-CoA, or as other intermediaries of the Krebs cycle, which resides within the mitochondrial matrix. Reducing equivalents in the form of NADH and FADH pass electrons to complex I (NADH-ubiquinone oxidore-ductase) or complex II (succinate dehydrogenase) of the electron transport chain, respectively. Electrons pass from complex I and II to complex III (ubiquinol-cyto-chrome c oxidoreductase) and then to complex IV (cytochrome c oxidase) which accumulates four electrons and then tetravalently reduces O2 to water. Protons are pumped into the inner membrane space at complexes I, II and IV and then diffuse down their concentration gradient through complex V (FoFi-ATPase), where their potential energy is captured in the form of ATP. In this way, ATP formation is coupled to electron transport and the formation of water, a process termed oxidative phosphorylation (OXPHOS). 

Mitochondria can have different shapes, depending on the kind of cell they are in. The number of mitochondria present in a cell also varies with cell type and may range from a single large mitochondrion to thousands. The region inside the inner membrane is called the matrix. This is where the Krebs cycle that converts pyruvate into C02 and energy takes place, so it contains a lot of enzymes. Mitochondria contain ribosomes, small particles composed of RNA and protein that are the sites of protein synthesis. Mitochondria also contain their own special DNA. 

Inside the inner membrane of a mitochondrion is a viscous region known as the matrix (Fig. 1-9). Enzymes of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle and the Krebs cycle), as well as others, are located there. For substrates to be catabolized by the TCA cycle, they must cross two membranes to pass from the cytosol to the inside of a mitochondrion. Often the slowest or rate-limiting step in the oxidation of such substrates is their entry into the mitochondrial matrix. Because the inner mitochondrial membrane is highly impermeable to most molecules, transport across the membrane using a carrier or transporter (Chapter 3, Section 3.4A) is generally invoked to explain how various substances get into the matrix. These carriers, situated in the inner membrane, might shuttle important substrates from the lumen between the outer and the inner mitochondrial membranes to the matrix. Because of the inner membrane, important ions and substrates in the mitochondrial matrix do not leak out. Such permeability barriers between various subcellular compartments improve the overall efficiency of a cell. 

The mitochondrion is bounded by two pho-spholipid membranes. The outer membrane is freely permeable to molecules, including water, with a molecular weight of up to about 5000. The inner membrane is rich in membrane-bound proteins and consists, in terms of membrane area, of 50% phospholipid and 50% protein (Lenaz, 1988). Pyruvate dehydn>genase, a mitochondrial enzyme, is water soluble. The proteins of the respiratory chain, as well as ATP synthase, are all bound to the inner mitochondrial membrane. The enzymes of the Krebs cycle are water soluble, with the exception of succinate dehydrogenase. This enzyme is bound to the mitochondrial membrane, where it directly funnels electrons, via HAD, to the respiratory chain. 

The positions of entry of glucogenic components of the amino acids into the Krebs cycle are shown in Figure 8.10. The amino acids that can be oxidized to pyruvate can be converted to oxaloacetic acid (OAA), after which the carbon skeleton exits the mitochondrion in the form of malate and is converted to glucose. Amino acids that can be oxidized to a-ketoglutarate or to succinyl-CoA can be converted to OAA and then to glucose. 

The uiea cycle may be considered to be a mitochondrial pathway, as carbamyl phosphate synthase and ornithine transcarbamylase are mitochondrial enzymes however, the enzymes catalyzing subsequent steps of the pathway arc cytosolic-The steps leading to conversion of citrulline to ornithine occur in the cytosol. Hence, the pathway is shared by the mitochondrial and cytosolic compartments. The fumarate produced by the urea cycle is converted to malate by a cytoplasmic form of fumarase. Mittxihondrial fumarase is part of the Krebs cycle. Cytoplasmic malate can enter the mitochondrion by means of a transport system, such as the malate/phosphate exchanger or the ma ate/a-ketoglutaratc exchanger. These transport systems are membrane-bound proteins. 

Krebs cycle A biochemical cycle in the second stage of cellular respiration involving eight steps that complete the metabolic breakdown of glucose molecules to carbon dioxide. Acetyl CoA is combined with oxaloac-etate to form citric acid. Citric acid is then converted into a number of other chemicals, and carbon dioxide is released. The process takes place within the mitochondrion. Also called citric acid cycle or tricarboxylic acid (TCA) cycle. Conceived and published by British scientist Sir Hans Adolf Krebs in 1957. 

Krebs cycle Citric acid cycle, TCA cycle, the mitochondrial process by which acetyl groups from acetyl-CoA are oxidized to CO. The reducing equivalents are captured as NADH and FADH, which feed into the electron transport system of the mitochondrion to produce ATP via oxidative phosphorylation. 

Ketogenesis The production of ketone bodies by the liver in response to increased P-oxidation with a decreased rate of the Krebs cycle as a resnlt of shnttling acids from the mitochondrion for the synthesis of glncose via glnconeogenesis. 

Figure 15.1 The mitochondrion schematic diagram showing the inner membrane where most of aerobic ATP formation occurs and the matrix which is the site of fatty acid j8-oxidation, the Krebs cycle, etc. Each typical cell contains many mitochondria.

Probably, the ultimate case of symbiosis involves cellular inclusions called mitochondria and chloroplasts. Mitochondria are small cylindrical bodies within eukaryotic cells that function as the chemical powerhouses of these cells (see Sections 5.3.7 and 5.5.1). It is in the mitochondrion that ATP is formed through the biochanical reactions of the Krebs cycle (see Section 3.10). Mitochondria are self replicating within the cell and their numbers increase as cellular energy needs increase. They contain their own DNA (mtDNA) separate from the DNA in the ceU nucleus. 

Figure 29.1 shows that the high ratio of NADH NAD in the mitochondrion favours reduction of oxaloacetate to malate in the malate dehydrogenase reaction. It also restricts oxidation in the a-ketoglutarate dehydrogenase and isocitrate dehydrogenase reactions. The result is that Krebs cycle is inhibited. 

PDH is a complex of three enzymes located in the mitochondrion. It controls the rate of entry of pyruvate into Krebs cycle. 

The electrons freed during the oxidation of fatty acids or of the Krebs cycle metabolites are ultimately transferred to the electron transport chain. This transfer can best be achieved if the oxidizing system and the electron transport chain are maintained in close contact in their cellular structures. It is therefore not surprising that, with few exceptions, all the enzymes of the fatty acid oxidation pathway are found in mitochondria. It has not yet been possible to reconstruct the exact pattern of the integration of each of these enzymes within the mitochondrial structure. Available information suggests only that these enzymes are not freely soluble within the mitochondrion. However, they are not as tightly bound to the mitochondrial structure as the enzymes of the electron transport chain. 

Carnitine serves as a cofactor for several enzymes, including carnitine translo-case and acyl carnitine transferases I and II, which are essential for the movement of activated long-chain fatty acids from the cytoplasm into the mitochondria (Figure 11.2). The translocation of fatty acids (FAs) is critical for the genaation of adenosine triphosphate (ATP) within skeletal muscle, via 3-oxidation. These activated FAs become esterified to acylcamitines with carnitine via camitine-acyl-transferase I (CAT I) in the outer mitochondrial membrane. Acylcamitines can easily permeate the membrane of the mitochondria and are translocated across the membrane by carnitine translocase. Carnitine s actions are not yet complete because the mitochondrion has two membranes to cross thus, through the action of CAT II, the acylcar-nitines are converted back to acyl-CoA and carnitine. Acyl-CoA can be used to generate ATP via 3-oxidation, Krebs cycle, and the electron transport chain. Carnitine is recycled to the cytoplasm for fumre use. 

Actively respiring fungal cells possess a distinct mitochondrion, which has been described as the power-house of the cell (Fig. 4.2). The enzymes of the tricarboxylic acid cycle (Kreb s cycle) are located in the matrix of the mitochondrion, while electron transport and oxidative phosphorylation occur in the mitochondrial inner membrane. The outer membrane contains enzymes involved in lipid biosynthesis. The mitochondrion is a semiindependent organelle as it possesses its own DNA and is capable of producing its own proteins on its own ribosomes, which are referred to as mitoribosomes. 

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