Of mitochondria

Mitochondria Mitochondria are organelles surrounded by two membranes that differ markedly in their protein and lipid composition. The inner membrane and its interior volume, the matrix, contain many important enzymes of energy metabolism. Mitochondria are about the size of bacteria, 1 fim. Cells contain hundreds of mitochondria, which collectively occupy about one-fifth of the cell volume. Mitochondria are the power plants of eukaryotic cells where carbohydrates, fats, and amino acids are oxidized to CO9 and H9O. The energy released is trapped as high-energy phosphate bonds in ATR... 

Wefss, H., Friedrich, T, Hofliaus, G., and Preis, D., 1991. The respiratory-chain NADH dehydrogena.se (Complex I) of mitochondria. European Journal of Biochemistry 197 563—576. 

Azzi, A., and Chance, B. (1969). The energized state of mitochondria lifetime and ATP equivalence. Biocbim. Biophys. Acta 189 141-151. 

Protoanemonin, which has been isolated from Anemone pulsatilla and Ranunculus spp., was reported to inhibit root growth by slowing down metabolism and blocking mitosis 35). Erickson and Rosen 35) observed cytological effects in corn root tips at concentrations of 10M and lower. Cells undergoing division appeared to accumulate in the interphase or prophase stages. Metaphase, anaphase, and telophase stages were not observed. Cytoplasmic and vacuolar structures were disturbed and the presence of mitochondria could not be demonstrated in treated tissue. Thimann and Bonner 141) reported that protoanemonin was 10 to 30 times more inhibitory than coumarin in coleoptile and split pea stem tests, and that BAL prevented the inhibitory action. 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

BH3 domain) of the BH3-only proteins binds to other Bcl-2 family members thereby influencing their conformation. This interaction facilitates the release of cytochrome C and other mitochondrial proteins from the intermembrane space of mitochondria. Despite much effort the exact biochemical mechanism which governs this release is not yet fully understood. The release of cytochrome C facilitates the formation of the apoptosome, the second platform for apoptosis initiation besides the DISC. At the apoptosome which is also a multi-protein complex the initiator caspase-9 is activated. At this point the two pathways converge. 

Negative regulation of apoptosis is effected by inhibitor of apoptosis proteins. Another means of controling apoptosis is by altering the stabilization of mitochondria, which is largely determined by the interplay between the pro- and antiapoptotic members of the Bcl2 family [4]. 

The synthesis of virtually all proteins in a cell begins on ribosomes in the cytosol (except a few mitochondrial, and in the case of plants, a few chloroplast proteins that are synthesized on ribosomes inside these organelles). The fate of a protein molecule depends on its amino acid sequence, which can contain sorting signals that direct it to its corresponding organelle. Whereas proteins of mitochondria, peroxisomes, chloroplasts and of the interior of the nucleus are delivered directly from the cytosol, all other organelles receive their set of proteins indirectly via the ER. These proteins enter the so-called secretory pathway (Fig. 1). 

Transport signals can be of the import or the export type. Import signals are contained in proteins that are transported into the individual compartments of mitochondria (matrix, inner membrane, intramembrane compartment, outer membrane), peroxisomes (lumen, boundary membrane) and into the interior of... 

Histopathological examination shows the typical corelike lesions in a high proportion of muscle fibers in older patients this may amount to 100%. Most typically the cores are large and centrally-placed, but multiple cores may occur in the same fiber cross section. Most older patients show a striking predominance of type 1 (slow twitch oxidative) fibers and virtually all fibers with cores are type 1. Sometimes younger family members have more normal proportions of type 1 and type 2 fibers but, again, the cores are confined to the type 1 fibers. It is well established that muscle fiber types can interconvert due to altered physiological demands, and it is likely that fibers with cores convert to a basically slow twitch-oxidative metabolism to compensate for the fact that up to 50% of their cross sectional area may be devoid of mitochondria. 

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

Figure 10. Ragged-red fibers with peripheral accumulations of mitochondria in muscle from a patient with Kearns-Sayre syndrome (KSS).

Fatal infantile cytochrome c oxidase (CCO) deficiency is characterized by total absence of catalytic activity in skeletal muscle. This often occurs within the context of the Fanconi syndrome, or less commonly in association with a cardiomyopathy. Although the deficiency is global in skeletal muscle, with all fibers affected, only isolated scattered fibers show abnormal aggregations of mitochondria (ragged-red fibers). Multiple affected siblings within one family are frequently encountered and suggest autosomal recessive inheritance. The condition normally proves fatal before the age of six months and is characterized by worsening intractable lactic acidemia. 

In be complexes bci complexes of mitochondria and bacteria and b f complexes of chloroplasts), the catalytic domain of the Rieske protein corresponding to the isolated water-soluble fragments that have been crystallized is anchored to the rest of the complex (in particular, cytochrome b) by a long (37 residues in bovine heart bci complex) transmembrane helix acting as a membrane anchor (41, 42). The great length of the transmembrane helix is due to the fact that the helix stretches across the bci complex dimer and that the catalytic domain of the Rieske protein is swapped between the monomers, that is, the transmembrane helix interacts with one monomer and the catalytic domain with the other monomer. The connection between the membrane anchor and the catalytic domain is formed by a 12-residue flexible linker that allows for movement of the catalytic domain during the turnover of the enzyme (Fig. 8a see Section VII). Three different positional states of the catalytic domain of the Rieske protein have been observed in different crystal forms (Fig. 8b) (41, 42) ... 

In contrast to common usage, the distinction between photosynthetic and respiratory Rieske proteins does not seem to make sense. The mitochondrial Rieske protein is closely related to that of photosynthetic purple bacteria, which represent the endosymbiotic ancestors of mitochondria (for a review, see also (99)). Moreover, during its evolution Rieske s protein appears to have existed prior to photosynthesis (100, 101), and the photosynthetic chain was probably built around a preexisting cytochrome be complex (99). The evolution of Rieske proteins from photosynthetic electron transport chains is therefore intricately intertwined with that of respiration, and a discussion of the photosynthetic representatives necessarily has to include excursions into nonphotosynthetic systems. 

Generally, NAD-linked dehydrogenases catalyze ox-idoreduction reactions in the oxidative pathways of metabolism, particularly in glycolysis, in the citric acid cycle, and in the respiratory chain of mitochondria. NADP-linked dehydrogenases are found characteristically in reductive syntheses, as in the extramitochon-drial pathway of fatty acid synthesis and steroid synthesis—and also in the pentose phosphate pathway. 

Figure 12-2. Role of the respiratory chain of mitochondria in the conversion of food energy to ATP. Oxidation of the major foodstuffs leads to the generation of reducing equivalents (2H) that are collected by the respiratory chain for oxidation and coupled generation of ATP.

The rate of respiration of mitochondria can be controlled by the availability of ADP. This is because oxidation and phosphorylation are tightly coupled ie, oxidation cannot proceed via the respiratory chain without concomitant phosphorylation of ADP. Table 12-1 shows the five conditions controlling the rate of respiration in mitochondria. Most cells in the resting state are in state 4, and respiration is controlled by the availability of ADP. When work is performed, ATP is converted to ADP, allowing more respiration to occur, which in turn replenishes the store of ATP. Under certain conditions, the concentration of inorganic phosphate can also affect the rate of functioning of the respiratory chain. As respiration increases (as in exercise). 

The reduced coenzymes are oxidized by the respiratory chain linked to formation of ATP. Thus, the cycle is the major route for the generation of ATP and is located in the matrix of mitochondria adjacent to the enzymes of the respiratory chain and oxidative phosphorylation. 

Figure 17-1. Summary of glycolysis. 0, blocked by anaerobic conditions or by absence of mitochondria containing key respiratory enzymes, eg, as in erythrocytes.

Carnitine (p-hydroxy-y-trimethylammonium butyrate), (CHjljN"—CH2—CH(OH)—CH2—COO , is widely distributed and is particularly abundant in muscle. Long-chain acyl-CoA (or FFA) will not penetrate the inner membrane of mitochondria. However, carnitine palmitoyltransferase-I, present in the outer mitochondrial membrane, converts long-chain acyl-CoA to acylcarnitine, which is able to penetrate the inner membrane and gain access to the P-oxidation system of enzymes (Figure 22-1). Carnitine-acylcar-nitine translocase acts as an inner membrane exchange transporter. Acylcarnitine is transported in, coupled with the transport out of one molecule of carnitine. The acylcarnitine then reacts with CoA, cat-... 

Another condition due to mutations in the RYRl gene is central core disease. This is a rare myopathy presenting in infancy with hypotonia and proximal muscle weakness. Electron microscopy reveals an absence of mitochondria in the center of many type I (see below) muscle fibers. Damage to mitochondria induced by high intracellular levels of Ca secondary to abnormal functioning of RYRl appears to be responsible for the morphologic findings. 

Ionophoretic Activity. PTX, even at high concentrations, had no ionophoretic activity on membranes of mitochondria and liposomes. 

In vivo, patients treated with AZT develop a mitochondrial myopathy with mitochondrial DNA depletion, deficiency of cytochrome c oxidase (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion (Lewis and Dalakas 1995 Dalakas 2001). Clinically, the patient presents with fatigue, myalgia, muscle weakness, wasting and elevated serum creatine kinase. Muscle biopsy shows ragged red fibers , the characteristic histopathologic changes of mitochondrial myopathy, cansed by subsarcolemmal accumulation of mitochondria (Lewis and Dalakas 1995). 

MAO is bound to the outer membrane of mitochondria and is responsible for the oxidative deamination of noradrenaline. There are two isoforms of this enzyme, MAO-A... 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

This essay was written in an attempt to explain our overview of primary cell walls and to reach consensus on the nomenclature of primary cell wall polysaccharides. We present evidence supporting the hypothesis that cellulose, xyloglucan, arabinoxylan, homogalacturonan, RG-I, and RG-II are the six polysaccharides common to all primary cell walls of higher plants. In many cells, these six polysaccharides account for all or nearly all of the primary wall polysaccharides. Like the physically interacting proteins that constitute the electron transport machinery of mitochondria, the structures of the six patently ubiquitous polysaccharides of primary cell walls have been conserved during evolution. Indeed, we hypothesize that the common set of six structural polysaccharides of primary cell walls have been structurally... 

A sequence of ten amino acids (ICS-D-KTGTLT) around the phosphorylation site of Na,K-ATPase (Asp ) is highly conserved among the Na,K-, H,K-, Ca-, and Id-pumps [6]. There is also homology with the subunit of FpATP synthetase of mitochondria and chloroplasts (see [6]) except that Asp is replaced by Thr. Accordingly a covalent phosphorylated intermediate is not formed in Fi-ATPase. Mutagenesis of the phosphorylated aspartate residue in Na,K-ATPase [82], Ca-ATPase [87], or H-ATPase [88] completely blocks activity. 

McKeage, M.J., Maharaj, L. and Berners-Price, S.J. (2002) Mechanisms of cytotoxicity and antitumor activity of gold(I) phosphine complexes the possible role of mitochondria. Coordination Chemistry Reviews, 232, 127—135. 

In recent studies on perfused rats hearts (Veitch et al., 1992), it was found that differences in the sensitivity of complexes 1-lV to ischaemic damage were dependent upon the duration of ischaemia and the presence of oxygen. The demonstration that complex 1 is a major defective site dependent upon isolation of mitochondria from homogenates of the tissue by in vitro methods seemed important to us. We therefore decided to attempt to make noninvasive measurements of mitochondrial function soon after reperfusion in transplanted rabbit kidneys by surface fluorescence (for mitochondrial NADH levels) and near infra-red spectroscopy (NIRS) for the redox state of cytaas. 

Moser CC, Farid TA, Chobot SE, Dutton PL. 2006. Electron tunneling chains of mitochondria. Biochim Biophys Acta 1757 1096-1109. 

Adenylate kinase (AK) is a ubiquitous monomeric enzyme that catalyzes the interconversion of AMP, ADP, and ATP. This interconversion of the adenine nucleotides seems to be of particular importance in regulating the equilibrium of adenine nucleotides in tissues, especially in red blood cells. AK has three isozymes (AK 1,2, and 3). AK 1 is present in the cytosol of skeletal muscle, brain, and red blood cells, and AK 2 is found in the intermembrane space of mitochondria of liver, kidney, spleen, and heart. AK 3, also called GTP AMP phosphotransferase, exists in the mitochondrial matrix of liver and heart. 

---