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Cell Mitochondria: the Citric Acid Cycle and Oxidative Phosphorylation

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Cell Mitochondria: the Citric Acid Cycle and Oxidative Phosphorylation Cell Mitochondria: The Citric Acid Cycle and Oxidative Phosphorylation Dr. Fawwaz Al-Joudi PHM142 Oct 22 What are Mitochondria? • These are cytoplasmic organelles that carry the task of oxidation of the final products of metabolism using the oxygen breathed in. What do Mitochondria do? Mitochondria perform the task of oxidation of the final products of metabolism using the oxygen breathed in. Two major metabolic tasks are carried out in mitochondria, namely the tricarboxylic acid cycle and oxidative phosphorylation General Structure of Mitochondria • Two lipid bilayer membranes: • Outer membrane – smooth, contains large pores (porin channels) • Inner membrane – impermeable (even to H+), folded into cristae to increase surface area. Enzymes of the respiratory chain are embedded in the inner mitochondrial membrane • Matrix: this is the innermost space of the mitochondria which is enclosed by inner membrane. It contains mitochondrial DNA and ribosomes. It is the site of Kreb’s cycle and acetyl-CoA production. • Intermembrane space: this is the area between the two membranes where the oxidative phosphorylation apparatus is situated. Mitochondrial structure Origin of mitochondria: the endosymbiont hypothesis • Evidence suggests that mitochondria have evolved from bacteria which were phagocytosed by an anaerobic, nucleus-containing eukaryotic cells. • These “bacterial ancestors” that live in eukaryotic cells are called “endosymbionts”. 6 Mitochondria: the power houses • Mitochondria are organelles that act like a cellular digestive system that takes in nutrients, breaks them down, and creates energy for the cell. • The process of creating cell energy is known as cellular respiration and most of the chemical reactions involved in cellular respiration take place in the mitochondria. • The mitochondria are very small organelles yet they are shaped perfectly to maximize their hard work The citric acid cycle (CAC): An OVERVIEW • The Citric Acid Cycle (CAC: also called the Kreb’s cycle or the ticarboxylic acid cycle) plays several roles in metabolism since it is the final pathway where the oxidative metabolism of carbohydrates, amino acids, and fatty acids converge, their carbon skeletons being converted to CO2. • This oxidation provides energy for the production of the majority of ATP in most animals, including humans. • The CAC occurs totally in the mitochondria and is, therefore, in close proximity to the reactions of electron transport, which oxidize the reduced coenzymes produced by the cycle. The CAC: an overview • The citric acid cycle is a sequence of reactions in mitochondria that oxidizes the acetal moiety of acetyl-CoA to CO2 and reduces coenzymes that are re- oxidized through the electron transport chain linked to the formation of AT P. • The CAC is the final common pathway for the oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolised to acetyl-CoA or intermediates of this cycle. • It also has a central role in gluconeogenesis, lipogenesis and conversion of amino acids. • This cycle is not be viewed as a closed circle, but instead as a traffic circle with compounds entering and leaving as required, making it a central pathway of energy metabolism. The CAC is a central part in metabolism The major metabolic pathways The intracellular location and overview of the major metabolic pathways in a liver parenchymal cell. (Harper’s Illustrated Biochemistry, 30th Ed) The pyruvate produced in a eukaryotic cell • In eukaryotic cells, the pyruvate molecules produced at the end of glycolysis, are transported into mitochondria, which are sites of the citric acid cycle (mitochondrial matrix) and cellular respiration (inner membrane). • If oxygen is available, aerobic respiration will go forward. The TCA in brief The cycle starts was reaction between the acetyl moiety of acetyl-CoA and the four carbon dicarboxylic acid, oxaloacetate, forming a 6- carbon tricarboxylic acid, citrate. In the subsequent reactions, two molecules of CO2 are released and oxaloacetate is regenerated. Also, two NADH molecules and one FADH2 molecule are liberated: these will then be utilized by the ETC in the oxidation process and ATP generation. TCA: the cycle • The citric acid cycle is a closed loop in the sense that the last part of the pathway regenerates the compound used in the first step. • The eight steps of the cycle are a series of chemical reactions that produces: - two carbon dioxide molecules, - one ATP molecule (or an equivalent), and + + - reduced forms (NADH and FADH2) of NAD and FAD , important coenzymes in the cell. Pyruvate in mitochondria • Pyruvate is transported into the mitochondria using a specific pyruvate transporter that helps pyruvate cross the inner mitochondrial membrane. • Once in the matrix, pyruvate is converted to acetyl CoA by the pyruvate dehydrogenase enzymes Complex. • Deficiency of this complex is a major cause of congenital lactic acidosis which is an X-linked trait. Reactions of the CAC: starting from Acetyl CoA and ending up with oxaloacetate • A. Synthesis of citrate, a six-carbon molecule, from the condensation of acetyl CoA and oxaloacetate is catalyzed by citrate synthase. • B. lsomerization of citrate to isocitrate by aconitase, an Fe-S protein. One NADH+ molecule is formed. • N.b. The poison fluoracetate is found in some plants, and their consumption can be fatal to grazing animals. Some fluorinated compounds used as anti cancer agents and industrial chemicals (such as pesticides), are metabolised to fluoroacetate. Fluoro acetyl-CoA condenses with oxaloacetate to form fluorocitrate which inhibits aconitase stopping the cycle and causing citrate to accumulate. The Citric Acid Cycle (Harper’s Illustrated Biochemistry, 30th Ed) Followed by: • C. Oxidation and decarboxylation of isocitrate by isocitrate dehydrogenase to give α-ketoglutarate. • D. Oxidative decarboxylation of α-ketoglutarate, catalyzed by the α- ketoglutarate dehydrogenase complex to give succinyl CoA. Mg+ or Mn+ ions are required for this reaction. • The reaction releases the second CO2 and produces the second NADH of the cycle. • This step is arsenite-sensitive. • By all means, hyperammonaemia inhibits the α-ketoglutarate dehydrogenase complex. Then • E. Conversion of succinyl CoA to succinate by Succinate thiokinase which cleaves the high-energy thioester bond of succinyl CoA. • This reaction is coupled to phosphorylation of guanosine diphosphate (GDP) to guanosine triphosphate (GTP). GTP and ATP are energetically interconvertible by the nucleoside diphosphate kinase reaction: GTP + ADP GDP + ATP The Citric Acid Cycle (Harper’s Illustrated Biochemistry, 30th Ed) The last steps • F. Oxidation of succinate to fumarate by succinate dehydrogenase, producing the reduced coenzyme FADH2. • G. Hydration of fumarate to malate by fumarase. • H. Oxidation of malate to oxaloacetate by malate dehydrogenase. Vitamins essential for the CAC • Four of the B vitamins are essential in the citric acid cycle: • 1- Riboflavin in the form of flavin adenine dinucleotide (FAD),a cofactor of succinate dehydrogenase . • 2- Niacin, in the form of nicotine amide adenine dinucleotide (NAD+), the electron acceptors for isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase. • 3- Thiamin (vitamin B1), as thiamine diphosphate, the coenzyme for decarboxylation in the α-ketoglutarate dehydrogenase reaction . • 4- Pantothenic acid , as part of coenzyme A, the cofactor esterified to active carboxylic acid residues: acetyl-CoA and succinyl-CoA. REGULATION OF THE TCA CYCLE • The TCA cycle is controlled by the regulation of several enzyme activities. • The most important of these regulated enzymes are those that catalyze reactions are isocitrate synthase, isocitrate dehydrogenase, and a-ketoglutarate dehydrogenase complex. • Reducing equivalents needed for oxidative phosphorylation are generated by the pyruvate dehydrogenase complex and the TCA cycle, and both processes are upregulated in response to a rise in A DP. Inhibitors and activators of the CAC (Lippincott’s Illustrated Reviews: Biochemistry, 4th Ed.) The Respiratory Chain and Oxidative Phosphorylation Mitochondria. (a). A living fibroblast with a phase contrast microscope where mitochondria are seen as elongated dark bodies (b). TEM of a thin section through a mitochondrion revealing the internal structure of the organelle. (c) localization of mitochondria in the midpiece surrounding the proximal portion of the flagellum of a bat sperm. (Karp’s Cell and Molecular Biology, 9th Ed.) Structure of the Mitochondria (Harper’s Illustrated Biochemistry, 30th Ed) The mitochondrial matrix is enclosed by a double membrane. Inner membrane has cristae that vastly increase the surface area inside the organelle. The outer membrane is permeable to most metabolites and the inner membrane is selectively permeable. The phospholipid cardiolipin is concentrated in the inner membrane together with the enzymes of the respiratory chain and ATP synthase. The electron transport chain (ETC): • It is the last component of aerobic respiration and • In ETC, energy is produced by transferring electrons down a chain of molecules along with various enzymes located on the inner membrane. • It is the only part of metabolism that uses atmospheric oxygen which enters through the respiratory system. • The mitochondria are the only places in the cell where oxygen can be combined with the food molecules (products) to provide the cell with usable energy molecules (ATP). Mitochondrial
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