Nucleus Oxidative phosphorylation

Not all the cellular DNA is in the nucleus some is found in the mitochondria. In addition, mitochondria contain RNA as well as several enzymes used for protein synthesis. Interestingly, mitochond-rial RNA and DNA bear a closer resemblance to the nucleic acid of bacterial cells than they do to animal cells. For example, the rather small DNA molecule of the mitochondrion is circular and does not form nucleosomes. Its information is contained in approximately 16,500 nucleotides that func-tion in the synthesis of two ribosomal and 22 transfer RNAs (tRNAs). In addition, mitochondrial DNA codes for the synthesis of 13 proteins, all components of the respiratory chain and the oxidative phosphorylation system. Still, mitochondrial DNA does not contain sufficient information for the synthesis of all mitochondrial proteins most are coded by nuclear genes. Most mitochondrial proteins are synthesized in the cytosol from nuclear-derived messenger RNAs (mRNAs) and then transported into the mito-chondria, where they contribute to both the structural and the functional elements of this organelle. Because mitochondria are inherited cytoplasmically, an individual does not necessarily receive mitochondrial nucleic acid equally from each parent. In fact, mito-chondria are inherited maternally. 

The existence of mitochondrial DNA, ribosomes, and tRNAs supports the hypothesis of the endosymbiotic origin of mitochondria (see Fig. 1-36), which holds that the first organisms capable of aerobic metabolism, including respiration-linked ATP production, were prokaryotes. Primitive eukaryotes that lived anaerobically (by fermentation) acquired the ability to carry out oxidative phosphorylation when they established a symbiotic relationship with bacteria living in their cytosol. After much evolution and the movement of many bacterial genes into the nucleus of the host eukaryote, the endosymbiotic bacteria eventually became mitochondria. 

Usnic acid (498), a modified benzofuran, occurs in many species of Cetraria and Cladonia and strongly inhibits the growth of many Gram positive organisms (50JA1819). Several reports suggest that it works by interfering with oxidative phosphorylation in the nucleus and in... 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

In addition to their plasma membrane eukaryotic cells also contain internal membranes that define a variety of organelles (fig. 17.2). Each of these organelles is specialized for particular functions The nucleus synthesizes nucleic acids, mitochondria oxidize carbohydrates and lipids and make ATP, chloroplasts carry out photosynthesis, the endoplasmic reticulum and the Golgi apparatus synthesize and secrete proteins, and lysosomes digest proteins. Additional membranes divide mitochondria and chloroplasts into even finer, more specialized subcompartments. Like the plasma membrane, organellar membranes act as barriers to the leakage of proteins, metabolites, and ions they contain transport systems for import and export of materials, and they are the sites of enzymatic activities as diverse as cholesterol biosynthesis and oxidative phosphorylation. 

MITOCHONDRION A membrane-bound organelle of eukaryotic organisms that replicates independently of the cell nucleus and contains its own ENA and its own protein-synthesizing apparatus its function is to provide energy to the cell in the form of adenosine triphosphate by oxidative phosphorylation. 

The first sub-cellular organelle to be isolated (other than the nucleus), mitochondria are the powerhouse of the cell, generating ATP through aerobic oxidative phosphorylation the TCA (Krebs) cycle (the hub of metabolism ) and fatty acid oxidation take place entirely within mitochondria. Other pathways and cycles (urea cycle, haem biosynthesis, cardiohpin synthesis, quinone and steroid biosynthesis) include steps both outside and inside the mitochondria. 

Leptin acts on receptors in the arcuate nucleus of the hypothalamus, causing the release of anorexigenic peptides, including a-MSH, that act in the brain to inhibit eating. Leptin also stimulates sympathetic nervous system action on adipocytes, leading to uncoupling of mitochondrial oxidative phosphorylation, with consequent thermogenesis. 

When they further observed that the normal nucleus contains a high proportion of mono-, di-, and trinucleotides of adenine, they claimed to have provided direct proof of their theory by demonstrating that the mono-or dinucleotides in the nucleus may be converted to ATP when oxygen is present. (The nucleotides can be extracted from the nucleus with acetate buffer at pH 5.1.) This conversion certainly suggested the existence of an intranuclear process of oxidative phosphorylation. As in mitochondria, oxidative phosphorylation in the nucleus is inhibited by uncouplers or agents blocking the electron transport chain. Nuclear oxidative phosphorylation is blocked by cyanide, azide, and antimycin A, or by dinitrophenol but, in contrast to mitochondria, it is resistant to Janus green, methylene blue, carbon monoxide, Dicumarol, and calcium. 

Nuclear oxidative phosphorylation is difficult to quantify. Although oxygen uptake in the nucleus can be measured, no exact P/O ratio is available. This is because only the AMP already present in the nuclear preparation can be converted to ATP any AMP added to the nuclei remains unaltered. An intriguing observation is the effect of DNase on the phosphorylation of AMP. (Allfrey has proposed that DNase blocks ATP synthesis in the nucleus indirectly namely, by inhibition of the nuclei by the histones, which after DNA extraction are no longer associated with DNA by salt linkages [35].) The enzymic extraction of 55% of the DNA in the nucleus leads to the loss of nuclear phosphorylation properties, which can be restored by adding DNA to the system. The effect of DNA is not specific because DNA can be replaced by RNA, polyadenylic acid, heparin, chondroitin sulfate, and polyethylene sulfate. Oxidative phosphorylation in thymus nuclear preparation has been confirmed in two laboratories. Whole body doses of ionizing radiation inhibited oxidative phosphorylation in thymus nuclei. 

It remains to be established, however, that this peculiar phosphorylating system is native to the nucleus and does not represent contamination of the nuclear fraction by intact cells or by intact or fragmented mitochondria. The arguments against mitochondrial contamination rest on several observations. Among them are the absence of cytochrome oxidase in nuclei and the difference between nuclear and mitochondrial oxidative phosphorylation with respect to their responses to inhibitors. 

Betel, I., Klouwen, H.M. Oxidative phosphorylation in nuclei isolated from rat thymus. In The cell nucleus-metabolism and radiosensitivity. Proc. Int. Symp., p. 281-293. London Taylor and Francis 1966... 

Ubiquinones (UQ), often called coenzyme Qio, are electron carriers in oxidative phosphorylation and photosynthesis, respectively. Ubiquinones consist of quinoid nucleus (derived from the shikimate pathway), 4-hydroxybenzoate (derived from chorismate or tyrosine), and terpenoid moiety. Zeatin, a phytohormone, is a member of the cytokinin family involved in various processes of growth and development in plants. Most cytokinins are adenine-type, where the hydrogen of amino group at Ce position of adenine is replaced with an isoprenoid. 

Fig. 2.2 Simplified scheme of oxidant/antioxidant regulation ofNF-KB activation. Different stimuli, leading to an increase of ROS generation inside the ceU, activate the phosphorylation of IkB inhibitory protein and the subsequent proteolysis. Thioredoxin (Trx) may reduce activated NF-kB proteins facilitating nuclear translocation.Qnce released from IkB, the NF-kB complex translocates into the nucleus and the binding to DNA domain in the promoters and enhancers of genes such as TNF-a, IL-1, proliferation and chemotactic factors, adhesion molecule. Some of these genes, in turn, may further induce NF-kB activation, leading to a vicious circle if the regulatory cellular system escapes from...

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