Section IV Part 2 (Chapters 24-28) Flashcards
What is the mechanism by which re-oxidation of NADH + FADH2 via the ETC results in ATP synthesis?
ETC oxidizes NADH and FADH2 and donates e- to O2 while pumping protons across the inner mitochondrial membrane, the energy (electrochemical gradient) from the reduction of O2 to H2O is used to power ATP synthase/ F0F1-ATPase, which phosphorylates ADP to ATP
What phosphorylates ADP to ATP?
ATP synthase/ F0F1-ATPase
Where does ox phos occur?
Inner membrane of mitochondria
Components here: ATP synthase & ETC
Why does ox phos occur on the inner membrane of mitochondria?
To maintain a chemical gradient
How do electrons flow in ETC?
Electrons flow from NADH to NADH:CoQ oxidoreductase/complex I to coQ to cytochrome b-c1 complex (III) to cytochrome c to cytochrome c oxidase (IV)
How does oxidative phosphorylation occur?
Occurs from the reduction of O2 and generation of a chemical gradient that powers an ATP synthase to generate ATP
How does substrate-level phosphorylation occur?
Utilizes the release of high-energy bonds to phosphorylate an ADP molecule, accomplished without O2
What is the importance of iron, copper, and oxygen in the ETC?
The oxidation-reduction components of ETC = Complex I-IV, flavin mononucleotide (FMN) , Fe-S centers, CoQ, Fe in cytochrome b/c1/c/a/a3 and Cu in cytochrome a/a3
FMN accepts 2 e- from NADH and pass them to Fe-S centers that pass to CoQ
Fe atoms in cytochromes change from oxidated state (Fe3+) to reduced state (Fe2+)
Cu+ ions in cytochrome oxidase facilitate the collection of e- and reduction of O2
Proton motive force in ox phos: importance & generation
The movement of H+ across the impermeable membrane via action of the ETC ( chain of oxidation-reduction rxns with final e- acceptor = O2) creates an electrochemical gradient = proton motive force = potential energy of H+ reentering the matrix via ATP synthase = oxidative phosphorylation
What is 30% of energy from NADH/FADH2 oxidation by O2 used for?
ATP synthesis
What is 70% of energy from NADH/FADH2 oxidation by O2 used for?
Transport anion and Ca2+ into mitochondria
Released as HEAT
Glycerol 3-phosphate shuttle
In the cytosol, NADH is reoxidized to NAD+ by transferring e- to DHAP to make glycerol 3-P, which can be shuttled through the mitochondrial membranes via Glycerol 3-P shuttle; e- is donated to FAD and (eventually) donated to coQ
Malate-aspartate shuttle
NADH can transfer e- to cytosolic oxaloacetate to form malate which is transported via Malate-aspartate shuttle into matrix and malate is oxidized back to oxaloacetate to generate NADH; OA can convert to aspartate to pass back into cytosol
What hampers ETC & ATP production?
Deficiencies in iron, riboflavin, or niacin
What are iron, riboflavin, or niacin in terms of ETC & ATP production?
Coenzymes
Iron is necessary for…
Fe-S centers and redox reactions
Riboflavin is part of…
FAD, a coenzyme succinate DH, ETF-CoQ oxidoreductase & glycerol 3-phosphate DH
Riboflavin is also a
Electron acceptor that donates to the ETC
Niacin is a part of…
NAD, which is an E-acceptor that donates to ETC
Energy yield for glycolysis (aerobic v anaerobic)
BOTH produce 2 ATP, 2 NADH, and 2 pyruvates from one glucose molecule
Anaerobic glycolysis can … produce 2 ATP, since NADH is recycled to … and pyruvate is reduced to…
Only, NAD+, lactate
Aerobic glycolysis can continue to…
Oxidize pyruvate to acetyl CoA then to TCA
How much ATP can be formed via aerobic glycolysis
30-32 ATP
OXPHOS disease is caused by
Mutations in mitochondrial DNA
What is the mechanism for OXPHOS disease?
MtDNA codes for 13 subunits of the ETC complexes and mt mRNA/rRNA/tRNA; mutated mtDNA will hamper proper oxidative phosphorylation = OXPHOS diseases
What is the mode of inheritance of OXPHOS disease?
Mutated mtDNA comes from maternal inheritance, replicative segregation, threshold expression, high mtDNA mutation rate and accumulation of mutations with age
What does uncoupling mean in respect to ox phos?
H+ leak back into matrix without going through ATP synthase, which dissipates the electrochemical gradient without ATP production
Physiologic uncouplers (UCPs)
Channels in membrane that conduct H+ from intermembrane space to matrix to generate HEAT
Chemical uncouplers (Proton Ionophores)
Hydrophilic compounds that transport intermembrane H+ back into the matrix, reducing the proton gradient, and reducing ATP synthesis
What is an example of the effect of physiologic uncouplers?
Thermogenin in brown fat
What is the mechanism of thermogenesis in brown fat?
Cold causes sympathetic nerves to release NE that activate lipase in brown fat
Brown fat expresses UCP1/thermogenin which can be activated to form channel which conduct H+ across membrane which generates HEAT via nonshivering thermogenesis
ETC inhibitors … the sequential e- flow from NADH/FADH2 to O2
Bind/block
Uncouplers…
Disturb the inner mitochondrial membrane, leading to leakage of H+ and loss of potential energy as heat
Rotenone, amytal inhibits
Transfer of electrons from complex I to coenzyme Q
Antimycin C inhibits
Transfer of electrons from complex III to cytochrome c
Carbon monoxide (CO) inhibits
Transfer of electrons from complex IV to oxygen
Cyanide (CN) inhibits
Transfer of electrons through complex IV to oxygen
Atractyloside inhibits
Inhibits the adenine nucleotide translocase (ANT)
Oligomycin inhibits
Inhibits proton flow through the F0 component of the adenosine triphosphate (ATP) synthase
Dinitrophenol inhibits
An uncoupler; facilitates proton transfer across the inner mitochondrial membrane
Valinomycin inhibits
A potassium ionophore; facilitates potassium ion transfer across the inner mitochondrial membrane
What situations may cause lactic acidosis?
EtOH consumption increases NADH levels = lactic acidosis
Hypoxia/anoxia/ischemia/cyanide/CO increase anaerobic glycolysis = more lactate
Deficient/inhibited TCA cycle enzymes prevent acetyl-CoA oxidation = increase pyruvate = lactate
mtDNA defects decrease ETC activity = more anaerobic glycolysis = more lactate
Lactic acidosis can result from inhibition of lactate use in gluconeogenesis
What is lactic acidosis?
Results from increased NADH/NAD+ ratio in tissue which directs pyruvate to LDH to generate lactate
Why can any functional impairment of ox phos cause lactic acidosis?
Impaired OXPHOS will push ATP production towards the anaerobic route = lactate production for NADH recycling
Inner mitochondrial membrane is
Impermeable to polar molecules
Outer mitochondrial membrane is
Permeable to small polar molecules
How can mitochondrial permeability cause cell death?
Increase Ca2+, phosphate, ROS, hypoxia lead to OPENING of mitochondrial permeability transition pore (MPTP) = large nonspecific pore through inner and outer mt membrane = H+, anions, cation flood in and mt swells and results in NECROSIS
What are examples of inner mitochondrial membrane transport?
Phosphate-malate exchange, citrate-malate exchange, aspartate-glutamate transporter
What allows small polar molecules to get through the outer mitochondrial membrane to get through?
Nonspecific pores = VDACs
Rotenone is a
Insecticide, fish poison
Amytal is a
Barbiturate
Antimycin is a
Bacterial product
Cyanide can be found in
Almond pits, other fruit pits, created by burning plastics
What are the indirect inhibitors of ETC?
Atractyloside: blocks transport of ADP from cytosol into mitochondrial matrix via Adenine Nucleotide Translocase (ANT, Fig. 21.14).
Oligomycin: blocks Fo proton channel; stops ATP formation
What compounds allow for inner mitochondrial membrane permeability?
Aspirin, pentachlorophenol (wood preservative), 2,4- dinitrophenol (DNP, by-product of TNT synthesis – and once used as a diet aid!)
Aspirin, pentachlorophenol, and DNP are what types of molecules?
hydrophobic weak acids!