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Transcript
NME2.31: ENERGY PRODUCTION AND MITOCHONDRIA 07/03/08 MITOCHONDRIA Highly mobile organelles present in most cells; up to 2000 in hepatocytes Each mitochondrion comprises two specialised membranes: o Outer membrane Contains many porin channels and lipolytic enzymes Covers the outside of the mitochondrion like a shell o Inner membrane Mostly impermeable except via specific transport proteins Site of electron transport and proton pumping (see below) Folded into numerous cristae increasing surface area Between the outer and inner membranes is a narrow area known as the inter-membrane space o Chemically equivalent to the cytosol; contains kinases utilising ATP The inner membrane encloses a central large space called the matrix o Contains many hundreds of enzymes including those involved in oxidation o Site of mtDNA replication, synthesis and utilisation LEARNING OUTCOMES Describe the fundamentals of energy transduction, the difference between oxidative phosphorylation and substrate level phosphorylation Substrate oxidation and oxidative phosphorylation occur within mitochondria to generate energy o Oxidation of pyruvate, ketone bodies and fatty acids generates acetyl-CoA and NADH o Acetyl-CoA is oxidised further in the TCA cycle to generate more NADH o NADH is degraded to NAD coupled to the generation of ATP Acetyl-CoA contains coenzyme-A which is derived from vitamin B5 NAD has a central nicotinamide ring derived from vitamin B3 THE TRICARBOXYLIC ACID (TCA) CYCLE The TCA cycle takes place inside the mitochondria of most cells o Involves a sequence of 8 reactions o Aerobic but does not directly require (gaseous) oxygen; uses water molecules Acetyl-CoA is fully oxidised to form CO2 and various energy-rich carrier molecules (e.g. NADH, FADH2) o Each cycle produces 3NADH, FADH2 and GTP from a single acetyl-CoA molecule o 3H2O is used in the process and 2CO2 molecules are produced as by-products Coenzyme-A is lost in step 1 of the cycle, re-used in step 4 and lost again in step 5 o Only the acetyl group undergoes oxidation The overall reaction equation is: o Acetyl-CoA + 3H2O 2CO2 + 3NADH + FADH2 + GTP 1. 2. 3. 4. 5. 6. 7. 8. Acetyl-CoA is linked with oxaloacetate to form citrate (a 6-carbon molecule) Citrate is converted to isocitrate Isocitrate is oxidised to α-ketoglutarate generating CO2 and NADH α-ketoglutarate is oxidised to succinyl-CoA generating CO2 and NADH Succinyl-CoA is converted to succinate generating GTP Succinate is oxidised to fumarate generating FADH2 Fumarate is converted to malate Malate is converted to oxaloacetate generating NADH OXIDATIVE PHOSPHORYLATION 1. 2. 3. 4. 5. Oxidative phosphorylation is the only step in oxidative catabolism to directly require gaseous oxygen o Electrons are transferred along a series of carriers in the electron transport chain o The energy from electron transport powers proton pumps which generate a proton gradient o Protons flow back down their electrochemical gradient coupled to the synthesis of ATP The electron transport chain involves five enzyme complexes along the inner mitochondrial membrane NADH dehydrogenase NADH is oxidised to NAD donating 2 electrons to the transport chain NADH ↔ NAD+ + H+ + 2e 4 protons are pumped into the inter-membrane space FADH2 dehydrogenase FADH2 is oxidised to FAD donating 2 electrons to the transport chain FADH2 ↔ FAD + 2H+ + 2e Ubiquinone transports electrons between complexes 1, 2 and 3 Cytochrome b-c1 Passage of 2 electrons through the complex pumps 4 protons out Cytochrome c transports electrons between complexes 3 and 4 Cytochrome oxidase 2 electrons are transported back into the matrix and couple with gaseous oxygen 2e- + 2H+ + ½O2 H2O 2 protons are pumped out ATP synthase 4 protons moving into the matrix power the phosphorylation of ADP ADP + Pi ATP ATP is produced for every 4 protons that flow down their electrochemical gradient One mole of NADH goes through steps 1 to 5 producing 2.5 ATP One mole of FADH2 goes through steps 2 to 5 producing 1.5 ATP Low ATP usage results in an accumulated proton gradient stopping electron transport THERMOGENESIS Heat can be generated in the body through uncoupling of ATP synthesis from NADH oxidation Allowing protons to ‘leak’ down their electrochemical gradient (from the inter-membrane space to the matrix) dissipates unused energy as heat This process is facilitated by chemical and protein uncouplers (UCPs) e.g. thermogenin o UCPs are highly regulated uncoupling proteins that generate heat There are various types of UCP: o UCP1 – found in brown fat i.e. primarily in infants around the neck, sternum, kidneys o UCP2 – ubiquitous o UCP3 – found in muscle o UCP4/5 – found in the brain