Download NME2.31 - Energy Production

NME2.31: ENERGY PRODUCTION AND MITOCHONDRIA
07/03/08
MITOCHONDRIA
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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
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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
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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
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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
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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
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Heat can be generated in the body through uncoupling of ATP synthesis from NADH oxidation
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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