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What is the main role of the electron transport chain and oxidative phosphorylation?

The electron transport chain transfers electrons from NADH and FADH₂ to oxygen, using the released energy to pump protons across the inner mitochondrial membrane. Oxidative phosphorylation uses the resulting proton gradient to make ATP.

What are the main structural compartments of a mitochondrion?

A mitochondrion has an outer membrane, an inner membrane folded into cristae, an intermembrane space, and a matrix. The inner membrane houses the electron transport chain and ATP synthase.

How do the outer and inner mitochondrial membranes differ in permeability?

The outer membrane is relatively leaky because porins allow small molecules to pass. The inner membrane is highly impermeable, including to protons and NADH, allowing a proton gradient to be maintained and requiring shuttles for cytosolic NADH electrons.

What is the function of mitochondrial cristae, and in which tissues are they especially abundant?

Cristae increase the surface area of the inner mitochondrial membrane for electron transport and ATP synthesis. They are especially prominent in high-energy tissues such as heart, muscle, brain, and ameloblasts.

Which metabolic pathways occur in the mitochondrial matrix, and which remain in the cytosol?

The matrix contains pyruvate dehydrogenase, the citric acid cycle, and fatty acid oxidation. Glycolysis and lactate dehydrogenase occur in the cytosol.

What are the key features of mitochondrial DNA described in the lecture?

Mitochondrial DNA is circular, encodes 13 electron-transport-chain proteins, and is inherited from the mother.

How many major complexes make up the electron transport chain, and what are the two mobile electron carriers?

The chain has four major complexes (I–IV). Coenzyme Q, also called ubiquinone, moves within the inner membrane, and cytochrome c moves along the outer face of the inner membrane.

What is the electron pathway through Complex I?

Complex I (NADH–Q oxidoreductase) accepts electrons from NADH, passes them to FMN and then iron–sulfur centres, and transfers them to coenzyme Q to form QH₂.

How many protons does Complex I pump, and why is it important?

Complex I pumps four H⁺ from the matrix to the intermembrane space as electrons pass from NADH to coenzyme Q. It is the main entry point for NADH generated by PDH and the citric acid cycle.

Which inhibitor blocks Complex I?

Rotenone blocks Complex I, preventing electron transfer from NADH toward coenzyme Q and reducing proton pumping and oxygen use.

What is Complex II, and how does it receive electrons?

Complex II is succinate dehydrogenase, the citric acid cycle enzyme that converts succinate to fumarate. Its FADH₂ passes electrons through iron–sulfur centres to coenzyme Q.

Why does Complex II pump no protons?

The energy released when FADH₂ electrons pass through Complex II to coenzyme Q is too small to drive proton pumping. FADH₂ electrons therefore enter the chain downstream of Complex I and yield less ATP than NADH electrons.

Which other mitochondrial enzymes can feed electrons directly into coenzyme Q?

Acyl-CoA dehydrogenase in fatty acid oxidation and mitochondrial glycerol-3-phosphate dehydrogenase also pass electrons to coenzyme Q, bypassing Complex I.

What is coenzyme Q and what is its role in the electron transport chain?

Coenzyme Q (ubiquinone) is lipid-soluble and diffuses within the inner mitochondrial membrane. It collects electrons from Complexes I and II and other FAD-linked enzymes, then carries them to Complex III.

What does Complex III do, and how many protons does it pump?

Complex III (Q–cytochrome c oxidoreductase) transfers electrons from QH₂ to cytochrome c and pumps four H⁺ into the intermembrane space.

What is cytochrome c and how does it carry electrons?

Cytochrome c is a small heme-containing protein on the outer face of the inner mitochondrial membrane. It carries one electron at a time from Complex III to Complex IV; its heme iron cycles between Fe³⁺ and Fe²⁺.

Which inhibitor blocks Complex III?

Antimycin A inhibits Complex III, interrupting transfer of electrons from coenzyme QH₂ to cytochrome c and reducing downstream electron flow and proton pumping.

What does Complex IV do with electrons, and why is oxygen essential?

Complex IV (cytochrome c oxidase) transfers electrons from cytochrome c to oxygen, the final electron acceptor. Oxygen combines with electrons and protons to form water; without oxygen the chain backs up.

What is the overall oxygen-reduction reaction at Complex IV?

O₂ + 4 e⁻ + 4 H⁺ → 2 H₂O. Complex IV pumps about two protons per electron pair as it transfers electrons to oxygen.

Which substances inhibit Complex IV, and how do they act?

Cyanide, azide, and carbon monoxide bind the heme–copper centre of cytochrome c oxidase and stop electrons from reaching oxygen. Cells can be unable to use oxygen even when blood oxygen is present.

How do reactive oxygen species arise during electron transport?

Some electrons leak from the chain, especially at Complexes I and III, and partially reduce oxygen to superoxide. Superoxide can be converted into hydrogen peroxide, which must then be detoxified.

How do cells detoxify superoxide and hydrogen peroxide?

Superoxide dismutase converts superoxide to hydrogen peroxide. Catalase or glutathione peroxidase then converts hydrogen peroxide to water. Glutathione used by glutathione peroxidase is kept reduced by NADPH.

Why are many strict anaerobic bacteria harmed by oxygen?

Many strict anaerobes lack sufficient superoxide dismutase and catalase. When oxygen is present, reactive oxygen species accumulate and damage their DNA, proteins, and membranes; they therefore survive best in low-oxygen niches.

What is the chemiosmotic hypothesis?

The chemiosmotic hypothesis states that electron transport and ATP synthesis are linked by a proton-motive force across the inner mitochondrial membrane. The proton gradient is the link between the chain and ATP synthase.

How do Complexes I, III, and IV create the proton-motive force?

Complexes I, III, and IV pump H⁺ from the matrix into the intermembrane space. This establishes both a pH difference and an electrical charge difference across the inner membrane.

What are the chemical and electrical components of the proton-motive force?

The chemical component is the pH gradient (difference in proton concentration). The electrical component is the charge difference created by moving positively charged protons across the membrane.

How many protons are pumped per pair of electrons from NADH and FADH₂?

NADH electrons pass through Complexes I, III, and IV, which pump 4 + 4 + 2 = 10 H⁺. FADH₂ electrons enter at Complex II or Q, bypassing Complex I, so Complexes III and IV pump 4 + 2 = 6 H⁺.

What is the overall structure of ATP synthase?

ATP synthase has an F₀ membrane portion that conducts protons and rotates, and an F₁ matrix-facing head with three α and three β subunits. The β subunits contain the catalytic sites that make ATP; a stator holds the head in place while the γ shaft turns.

How does proton flow through F₀ cause ATP synthase to rotate?

Protons enter a half-channel in the F₀ a subunit, bind to sites on the c-ring, and drive its rotation before leaving through a second half-channel. The rotating c-ring turns the γ shaft inside the F₁ head.

What is the binding-change mechanism of ATP synthase?

Each β subunit cycles through Loose, Tight, and Open conformations. The Loose state binds ADP and inorganic phosphate; the Tight state holds them and ATP forms; the Open state releases ATP and can accept new substrates.

Where is the energy from the proton gradient used in the binding-change mechanism?

The proton gradient drives rotation of the γ shaft, forcing the β subunits to change shape and release ATP from the Tight site. ATP formation from ADP and phosphate occurs with little additional energy input; release is the energy-demanding step.

How many ATP molecules are produced per full rotation of ATP synthase?

A full turn of the γ shaft cycles the three β subunits through their states and produces three ATP molecules.

Which inhibitor blocks the F₀ portion of ATP synthase?

Oligomycin blocks F₀ and prevents proton flow through ATP synthase. This stops ATP synthesis and causes electron transport and oxygen use to slow as the proton gradient builds.

What are the P/O ratios for NADH and FADH₂, and why do they differ?

NADH yields about 2.5 ATP per pair of electrons, while FADH₂ yields about 1.5 ATP. FADH₂ electrons enter at Q and bypass Complex I, so they drive pumping of 6 rather than 10 protons.

Why is approximately four protons required for each ATP delivered to the cytosol?

About three protons drive ATP synthase to produce one ATP, and approximately one additional proton enters with inorganic phosphate transported into the matrix. Together the cost is about four H⁺ per ATP delivered to the cytosol.

How much ATP is produced per glucose during complete aerobic oxidation?

About 30–32 ATP per glucose are produced with oxygen. The range depends on the shuttle used to transfer cytosolic NADH electrons into the mitochondrion; without oxygen, glycolysis yields only 2 ATP per glucose.

How is ATP yield distributed across glycolysis, PDH, and the citric acid cycle?

Per glucose, glycolysis directly produces 2 ATP and 2 cytosolic NADH; PDH produces 2 NADH; the citric acid cycle produces 2 GTP, 6 NADH, and 2 FADH₂. Oxidative phosphorylation converts the reduced carriers into most of the remaining ATP.

Why can cytosolic NADH not directly enter the mitochondrial electron transport chain?

The inner mitochondrial membrane is impermeable to NADH and has no NADH transporter. Shuttles transfer the electrons carried by cytosolic NADH into the mitochondrion while allowing cytosolic NAD⁺ to be regenerated.

How does the malate–aspartate shuttle transfer cytosolic NADH electrons?

In the cytosol, NADH reduces oxaloacetate to malate, regenerating NAD⁺. Malate enters the matrix in exchange for α-ketoglutarate and is oxidized back to oxaloacetate, producing matrix NADH that feeds Complex I. Oxaloacetate is transaminated to aspartate, which exits in exchange for glutamate and is converted back to oxaloacetate in the cytosol.

Which tissues mainly use the malate–aspartate shuttle, and how much ATP is each cytosolic NADH worth through it?

The malate–aspartate shuttle is used mainly in liver, heart, and kidney. It transfers electrons to matrix NADH, which enters at Complex I and yields about 2.5 ATP per cytosolic NADH.

How does the glycerol-3-phosphate shuttle transfer cytosolic NADH electrons?

Cytosolic glycerol-3-phosphate dehydrogenase uses NADH to reduce DHAP to glycerol-3-phosphate, regenerating NAD⁺. Mitochondrial glycerol-3-phosphate dehydrogenase transfers the electrons to FAD, then to coenzyme Q, bypassing Complex I.

Which tissues mainly use the glycerol-3-phosphate shuttle, and how much ATP is each cytosolic NADH worth through it?

Skeletal muscle and brain mainly use the glycerol-3-phosphate shuttle. Its electrons enter at coenzyme Q and bypass Complex I, so each cytosolic NADH yields about 1.5 ATP.

How do the malate–aspartate and glycerol-3-phosphate shuttles compare?

The malate–aspartate shuttle transfers electrons to matrix NADH and Complex I, yielding about 2.5 ATP per cytosolic NADH; it is prominent in liver, heart, and kidney. The glycerol-3-phosphate shuttle transfers electrons to FAD and then Q, yielding about 1.5 ATP; it is prominent in skeletal muscle and brain.

How does ATP leave the mitochondrial matrix, and how does ADP enter?

The ATP–ADP translocase exchanges one ATP⁴⁻ from the matrix for one ADP³⁻ from the cytosol. The exchange moves one net negative charge out and is driven by the membrane potential.

How does inorganic phosphate enter the mitochondrial matrix for ATP synthesis?

The phosphate carrier brings inorganic phosphate into the matrix together with one H⁺. This proton import contributes to the approximate four-proton cost per ATP delivered to the cytosol.

What happens when the ATP–ADP translocase is inhibited by atractyloside?

Atractyloside blocks the ATP–ADP translocase, preventing ADP from entering the matrix and ATP from leaving. ATP synthesis and oxygen use both fall.

How do electron transport chain inhibitors affect oxygen use and ATP synthesis?

Inhibitors that block electron flow or ATP export decrease both oxygen use and ATP synthesis because electron transport, proton pumping, and ATP production become restricted.

Which electron transport chain inhibitors act at Complexes I, III, and IV?

Rotenone inhibits Complex I; antimycin A inhibits Complex III; cyanide, azide, and carbon monoxide inhibit Complex IV. Each blocks electron flow and reduces oxygen consumption and ATP production.

How do oligomycin and atractyloside inhibit oxidative phosphorylation?

Oligomycin blocks the F₀ proton channel of ATP synthase. Atractyloside blocks the ATP–ADP translocase. Both lower ATP synthesis and, because the system can no longer usefully dissipate the proton gradient, lower oxygen use.

What is an uncoupler, and how does it affect oxygen use and ATP synthesis?

An uncoupler allows protons to return across the inner mitochondrial membrane without passing through ATP synthase. Electron transport and oxygen consumption increase, but ATP synthesis decreases and energy is released as heat.

How do 2,4-dinitrophenol, salicylate overdose, and UCP-1 act as uncouplers?

2,4-DNP is a lipid-soluble weak acid that carries protons across the inner membrane. Salicylate at toxic doses uncouples oxidative phosphorylation. UCP-1 (thermogenin) is a proton channel in brown fat that releases energy as heat, especially in newborns.

How do inhibitors differ from uncouplers in their effects on the electron transport chain?

Most inhibitors stop electron flow or ATP synthesis and lower both oxygen use and ATP production. Uncouplers do not stop the chain; they dissipate the proton gradient, causing oxygen use to rise while ATP synthesis falls and heat production increases.

Which electron transport chain complex is the exception for mitochondrial DNA-encoded subunits?

Complex II is the only electron transport chain complex described in the lecture as having no mitochondrial DNA-encoded subunits; its subunits are nuclear-encoded.

What inheritance pattern and tissue pattern are associated with mitochondrial DNA disorders?

Mitochondrial DNA is maternally inherited. Disorders such as MELAS can particularly affect tissues with high energy requirements, including muscle, brain, and other metabolically active tissues.

How do the speed and directionality of the two mitochondrial NADH shuttles compare?

The malate–aspartate shuttle uses membrane antiporters and is slower and one-way under the membrane-potential conditions described. The glycerol-3-phosphate shuttle has no membrane carriers, is faster and one-way, and helps maintain cytosolic NAD⁺ during bursts of muscle work.

What are the toxic effects of 2,4-dinitrophenol when it uncouples oxidative phosphorylation?

2,4-DNP carries protons across the inner mitochondrial membrane and dissipates the gradient. It was once marketed for weight loss, but excessive uncoupling can cause dangerous, potentially fatal hyperthermia as oxygen consumption rises and energy is released as heat.

What happens during salicylate uncoupling in aspirin overdose?

At toxic doses, salicylate uncouples oxidative phosphorylation. Oxygen consumption rises while ATP falls, and the patient may develop fever, sweating, and heat production.

What structural feature of Complex I is highlighted in the lecture?

Complex I is the largest electron transport chain complex and has an L-shaped structure, with one arm extending into the mitochondrial matrix.

How is Complex II positioned in the inner mitochondrial membrane?

Complex II is associated with the matrix face of the inner mitochondrial membrane and does not span the membrane as a proton pump. This helps explain why it transfers electrons to coenzyme Q without pumping H⁺.

How is glycogen structured?

Glycogen is a branched glucose polymer with α1→4 linkages along its chains and α1→6 linkages at branch points. Branches occur about every 8–12 glucose residues.

What are the reducing and non-reducing ends of glycogen, and which end do enzymes use?

Glycogen has one reducing end attached to a glycogenin protein core and many non-reducing ends. Glycogen synthase and glycogen phosphorylase work at non-reducing ends.

Why is glycogen highly branched?

Each branch creates another non-reducing end, allowing many enzymes to synthesize or release glucose simultaneously. Branching therefore speeds storage and breakdown and also helps keep glycogen soluble.

Where is glycogen stored, and approximately how much is present in liver and muscle?

Glycogen is stored as granules in liver and muscle. The lecture gives approximately 100 g in liver and 400 g in muscle.

What is the overall sequence for glycogen synthesis?

Glucose-6-phosphate is converted to glucose-1-phosphate, then activated as UDP-glucose. Glycogen synthase extends α1→4 chains, and the branching enzyme creates α1→6 branches.

What does phosphoglucomutase do during glycogen synthesis?

Phosphoglucomutase moves the phosphate from carbon 6 to carbon 1, converting glucose-6-phosphate to glucose-1-phosphate.

How is UDP-glucose formed, and why is it called an activated glucose donor?

UDP-glucose pyrophosphorylase combines glucose-1-phosphate with UTP to form UDP-glucose and pyrophosphate. Hydrolysis of pyrophosphate to two inorganic phosphates pulls the reaction forward; UDP-glucose then donates glucose to glycogen synthase.

What is the energetic cost of adding glucose to glycogen?

Approximately one UTP, equivalent to one ATP, is used for each glucose added to glycogen as UDP-glucose.

Why is glycogenin needed for glycogen synthesis?

Glycogen synthase cannot start a new glycogen chain from nothing. Glycogenin acts as a protein primer by attaching the first few glucose residues to itself, after which glycogen synthase can extend the chain.

What does glycogen synthase do, and why is it the key control point of synthesis?

Glycogen synthase transfers glucose from UDP-glucose to the C-4 hydroxyl at a non-reducing end, making α1→4 bonds. It is the rate-limiting regulated enzyme of glycogen synthesis.

What does the branching enzyme do during glycogen synthesis?

The branching enzyme removes a block of about seven glucose residues from the end of a chain and reattaches it through an α1→6 bond. This creates new non-reducing ends.

How does glycogen phosphorylase break down glycogen?

Glycogen phosphorylase uses inorganic phosphate to cleave α1→4 bonds from non-reducing ends, releasing glucose-1-phosphate. This is phosphorolysis rather than hydrolysis.

Why does glycogen phosphorylase save ATP during glycogen breakdown?

It uses inorganic phosphate to release glucose-1-phosphate, which is already phosphorylated. The cell does not need to spend ATP to phosphorylate that glucose before it enters metabolism.

Which cofactor does glycogen phosphorylase require?

Glycogen phosphorylase requires pyridoxal phosphate, derived from vitamin B6.

Why does glycogen phosphorylase stop before reaching a branch point?

Glycogen phosphorylase cannot cleave the α1→6 branch linkage and stops about four glucose residues before the branch point. The debranching enzyme must clear the branch so phosphorylase can continue.

What are the two activities of the glycogen debranching enzyme?

Its transferase activity moves three of the remaining four glucose residues to the end of another chain. Its α1→6-glucosidase activity hydrolyzes the last glucose at the branch point, releasing it as free glucose.

What forms of glucose are released during glycogen breakdown?

Most glucose residues (about 90%) are released as glucose-1-phosphate by phosphorylase. About 10%, the single glucose at each α1→6 branch point, are released as free glucose by the debranching enzyme.

What happens to glucose-1-phosphate after it is released from glycogen?

Phosphoglucomutase converts glucose-1-phosphate into glucose-6-phosphate. The glucose-6-phosphate can then enter glycolysis in muscle or be converted to free glucose in liver.

Why can liver glycogen help maintain blood glucose?

Liver contains glucose-6-phosphatase, which removes the phosphate from glucose-6-phosphate so free glucose can leave the cell and enter the blood. Liver glycogen supports blood glucose for the whole body.

Why can muscle glycogen not directly raise blood glucose?

Muscle lacks glucose-6-phosphatase. Glucose-6-phosphate derived from muscle glycogen remains in the muscle and enters glycolysis to support contraction.

How do liver and muscle glycogen stores differ in amount and function?

The liver stores about 100 g to help maintain blood glucose, while muscle stores about 400 g for its own energy needs. Liver glycogen typically supports blood glucose for about 12–18 hours of fasting; muscle glycogen is used during exercise.

How do liver and muscle differ in their hormonal response during glycogen breakdown?

The liver responds to glucagon and epinephrine. Muscle responds to epinephrine but lacks glucagon receptors, so glucagon does not directly activate muscle glycogen breakdown.

How does phosphorylation regulate glycogen phosphorylase and glycogen synthase?

Phosphorylation activates glycogen phosphorylase and inactivates glycogen synthase, switching breakdown on and synthesis off. Dephosphorylation has the opposite effect.

How does insulin reverse the phosphorylation state of glycogen-metabolizing enzymes?

Insulin promotes protein phosphatase-1 activity. Protein phosphatase-1 removes phosphate groups, activating glycogen synthase and inactivating glycogen phosphorylase so glycogen synthesis is favoured.

What is the hormone-signalling sequence that activates glycogen breakdown?

Glucagon in liver or epinephrine in liver and muscle binds a receptor and activates a G protein. The G protein stimulates adenylate cyclase, raising cAMP and activating PKA; PKA activates phosphorylase kinase, which activates glycogen phosphorylase.

How does PKA affect glycogen synthase during the glycogen-breakdown signal?

PKA also phosphorylates glycogen synthase and inactivates it. One hormone signal therefore activates glycogen breakdown while turning off glycogen synthesis.

Why does the glycogen hormone cascade amplify a signal?

Each activated component can activate many molecules of the next component in the cascade. A small amount of hormone can therefore lead to the breakdown of many glucose residues.

How do calcium and AMP promote glycogen breakdown in working muscle?

Ca²⁺ released during contraction activates phosphorylase kinase, helping activate glycogen phosphorylase. AMP rises when energy is low and activates glycogen phosphorylase directly.

Which signals inhibit glycogen breakdown in muscle?

ATP and glucose-6-phosphate indicate that energy and glucose intermediates are available and inhibit glycogen phosphorylase. This helps align glycogen breakdown with the muscle's actual energy demand.

How does blood glucose regulate liver glycogen breakdown?

High blood glucose inactivates liver glycogen phosphorylase, reducing glycogen breakdown when the blood already has enough glucose. Insulin also promotes glycogen synthesis through protein phosphatase-1.

How does glycogen metabolism change from the fed state to prolonged fasting?

After a meal, insulin activates glycogen synthesis and liver and muscle stores fill. Between meals and overnight, glucagon stimulates liver glycogen breakdown to maintain blood glucose. After about 12–18 hours, liver glycogen is depleted and gluconeogenesis increasingly takes over.

How can stress in a dental setting affect glycogen metabolism and blood glucose?

Anxiety can increase epinephrine, stimulating liver glycogen breakdown and raising blood glucose. This may worsen glucose control in a patient with diabetes on the day of treatment.

How do plaque bacteria use stored carbohydrate between meals?

Streptococcus mutans can store a glycogen-like intracellular polysaccharide when sugar is plentiful and ferment it to acid between meals.

What enzyme defect causes von Gierke disease, and what are its major consequences?

Von Gierke disease (glycogen storage disease I) is caused by glucose-6-phosphatase deficiency in liver and kidney. It causes severe fasting hypoglycemia, an enlarged liver, and lactic acidosis because glucose-6-phosphate cannot be released as free glucose.

What enzyme defect causes Pompe disease, and which tissues are affected?

Pompe disease (glycogen storage disease II) is caused by lysosomal α-glucosidase deficiency. Glycogen accumulates in multiple tissues, especially heart and muscle, causing cardiomegaly and muscle weakness.

What enzyme defect causes McArdle disease, and what happens during exercise?

McArdle disease (glycogen storage disease V) is caused by muscle glycogen phosphorylase deficiency. It causes exercise intolerance, cramps, and possible myoglobinuria, but blood glucose is usually normal because liver glycogen metabolism is intact.

How can glycogen storage disease symptoms be predicted from the affected tissue?

Liver defects impair blood-glucose support and cause fasting hypoglycemia. Muscle defects impair use of glycogen for contraction and cause exercise-related muscle symptoms, usually without hypoglycemia.

Why should a patient with a liver glycogen-storage disorder avoid fasting before dental treatment?

A patient with a liver disorder such as von Gierke disease may be unable to release glucose during fasting and can develop severe hypoglycemia. The lecture recommends treatment after a normal meal or usual feeding, early in the day, kept short, and coordinated with the physician and caregivers.

What are the phosphorylated forms of glycogen phosphorylase, and what is their activity state?

Phosphorylase a is the phosphorylated, active form of glycogen phosphorylase. Dephosphorylation converts it to phosphorylase b, the less active form; insulin and protein phosphatase-1 favour the dephosphorylated state.

How does liver glycogen content normally change across the day?

Liver glycogen rises after meals as glucose is stored and falls between meals and overnight as glycogen is broken down to support blood glucose. It is lowest before breakfast after the overnight fast.

Why does reciprocal phosphorylation prevent a futile cycle in glycogen metabolism?

The same phosphorylation signal activates glycogen phosphorylase while inactivating glycogen synthase. This coordinates breakdown and synthesis in opposite directions so the cell does not spend energy building glycogen while simultaneously breaking it down.