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*Synthesis is driven through an activated high energy intermediate in a sequence of two enzymatic reactions
* ATP synthesis is linked with electron transport chain and O₂ reduction to water
-No high-energy Intermediate is found
*ATP formed per atom equivalent of Oxygen (1/2 O₂) consumed, or ATP/2e⁻
*NADH oxidation ≈ 3
*Succinate oxidation ≈ 2
Coupling of ETC and ATP Synthase
*Respiratory control regulates the rate of electron transport and thus the rate of substrate oxidation and oxygen consumption
Coupling of Exergonic & Endergonic
*Dependent on each other
-Rate determined by slowest reaction
***IN Cell rate of respiration determined by the rate of ATP synthesis
ΔG = -nFΔE
*Energy required for ATP synthesis must be equivalent to energy released on ATP hydrolysis (ΔG = +14 kcal/mole for synthesis, -14 kcal/mole for hydrolysis)
*Using equation can be calculated that a reduction potential difference of at least 0.3 V is required
Reduction Potentials of Substrate Components
*Redox steps on right > potential difference to provide energy for ATP synthesis
*Consistent with P:O ratios (NADH 3:1 vs. Succinate 2:1)
*Coupling of electron transfer to ATP synthesis is indirect, via a H⁺ electrochemical gradient
*Spontaneous e⁻ transfer through complexes I, III, and IV is coupled to non-spontaneous H⁺ ejection from the mitochondrial matrix.
-H⁺ ejection creates a membrane potential (DY, negative in the matrix) and a pH gradient (DpH, alkaline in the matrix).
F₁F₀ ATP Synthase
*Non-spontaneous ATP synthesis is coupled to spontaneous H⁺ transport into the matrix compartment.
-The pH and electrical gradients created by respiration are together the driving force for H⁺ uptake.
-Return of protons to the matrix via F₀ "uses up" the pH and electrical gradients.
F₁F₀ ATPase-ATP-driven Proton Pump
*Protons required to drive pump
-3H⁺ per ATP synthesized (approximation)
Synthesis of ATP
*Involves the reversal of the ATP-linked pump by the PROTON GRADIENT generated by the respiratory chain
*Occurs w/ fall of ATP levels in Mitochondria
Reversal-of-proton-pump model for ATP synthesis readily accounts for:
*Effects of respiratory chain inhibitors (block electron transport
-Inhibit F₁F₀ ATPase
-Proton leakage back into Mitochondrial Matrix
-Ca⁺⁺ uptake by mitochondria
F₁ & F₀ Complexes
F₁ - Protruding into Matrix (Catalytic Activity)
F₀ - Transmembrane (Proton Channel)
Synthesis of ATP Steps
*Occurs on F₁ domain, while F₀ contains a proton channel
1)H⁺ Flow through structure ---> ring of c subunits & the rotor (γ) to turn
2)Conformational changes in the β subunits (catalytic sites located & ATP is synthesized)
3)αβ complex does not rotate
4)c subunits each contain an essential charged A.A. ---> Involved in proton pumping
*Role of proton pump is not to form ATP, but to release it from the synthase
Mitochondrial inner membranes contain substrate transport systems that facilitate selective movement of various substrates and intermediates back and forth across the membrane against a concentration gradient
Inner Membrane of Mitochondria
-Reactants & Products require membrane translocases
-Most translocases are electroneutral antiport systems
Electrogenic Transport Systems
*Influenced by a membrane potential
*Ca⁺⁺ taken up by mitochondria (electrogenic uniport)
*ATP leaves mitochondria by an electrogenic antiport w/ ADP
Adenine Nucleotide Translocase
*Adenine nucleotides (Very Highly Charged w/ hydrophobic ring)
-Catalyzed by specific ANTIPORTER (1:1 exchange of ATP for ADP
*Translocase favors OUTward movement of ATP & INward movement of ADP
*Membrane Potential Established (+ Outside favors outward transport of more - charged ATP
-Catalyzed by specific SYMPORT (1:1 exchange of phosphate and protons)
*Proton-motive force provides driving force for translocase
No Transporter In Mitochondrial Membrane for NAD...
*Therefore oxidation of cytosolic NADH produced during glycolysis occurs by use of substrates which can be readily oxidized by mitochondria
*Act on components of the respiratory chain
-Resulting in the inhibition of electron transport ---> ATP synthesis
*CN and CO inhibit cytochrome a₃ of Cytochrome Oxidase (Complex IV)
*Act on the enzymes of ATP synthesis
*Also inhibit electron transport (Since ATP synthesis determines the rate of electron transport
*Blocks synthesis of ATP
-Prevents movement of protons through the ATP synthase
*The "o" in F₁/F₀ ATPase stands for "oligomycin"
*Act on the coupled intermediates involved
-Result in an alternative pathway of energy dissipation
-Thus preventing ATP synthesis, but NOT electron transport
*2,4-dinitrophenol (Uncouple O₂ consumption and ATP synthesis)
*Uncouples O₂ consumption and ATP synthesis
*Hydrophobic weak acids ---> Protonated in intermembrane space (Higher [H⁺] resulting from active electron transport)
****Proton Gradient can be completely dissipated by the movement of protonated DNP into the Matrix
UCP1 (uncoupling protein 1, aka Thermogenin)
*Membrane spanning protein
-Permits influx of protons into mitochondria without formation of ATP
*Plays a role in generating heat in neonates
"Ancillary" Energy-Coupled Reactions
*Important processes which are associated with mitochondrial function
*Do NOT require ATP, but are coupled to electron transport & compete with ATP synthesis for the H⁺ gradient
Inhibition of Ancillary
*Respiratory inhibitors and uncouplers
*Unaffected by phosphorylation inhibitors
Ca⁺⁺ Uptake & Release in Mitochondria
*Important regulatory functions in the TCA
*Uptake is dependent on the H⁺ gradient
*HIGH [Ca⁺⁺] Leads To ---> pore formation, cytochrome c release and apoptosis
Mitochondrial transport of ATP & Amino Acid Aspartate
*Function: Maintains cytoplasmic ATP and NAD⁺ metabolic states
*Reduction of NADP⁺ by NADH
*Serves to maintain high levels of NADPH in the Mitochondria
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