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Questions and Answers
Parkinson's disease is one of the common disorders listed.
True
Leber hereditary optic neuropathy affects females four times more than males.
False
MELAS involves episodes of myopathy and lactic acidosis.
True
Leber hereditary optic neuropathy can cause lateral vision loss.
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Electrons flow through the electron transport chain to generate ATP.
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4 H+ equals 1 ATP generated.
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Electrons from NADH are not passed to the electron transport chain.
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Oxygen is the final electron donor in the electron transport chain.
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A proton gradient is established across the outer mitochondrial membrane.
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The Electron Transport Chain is located in the outer mitochondrial membrane.
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NADH and FADH2 are produced in the cytoplasm during glycolysis.
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ATP synthase utilizes the energy of H+ moving through a channel to produce ATP.
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The Chemiosmotic Hypothesis explains how ATP is generated from the energy released during electron transport.
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The energy from electrons in the Electron Transport Chain is only used to make ATP.
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Protons are moved from the intermembranous space back to the mitochondrial matrix through the F1 unit of ATP synthase.
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ATP is synthesized from ADP and Pi by the enzyme ATP Synthase.
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The TCA cycle occurs in the cytoplasm.
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The inner mitochondrial membrane is permeable to protons.
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Electrons from carbohydrates, triglycerides, and proteins ultimately flow to oxygen in the Electron Transport Chain.
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NADH and FADH2 are produced during the catabolism of carbohydrates, triglycerides, and proteins.
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The proton gradient completely prevents ATP synthesis in the Electron Transport Chain.
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Iron and vitamin deficiencies can lead to defects in electron transport.
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The chemiosmotic theory does not relate to ATP generation in the Electron Transport Chain.
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ADP and Pi are essential for ATP synthesis.
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Electrons from cytosolic NADH are directly transported into the mitochondrion.
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The glycerol 3-phosphate shuttle transfers electrons from cytosolic NADH to mitochondrial FAD.
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The malate-aspartate shuttle transfers electrons from NADH to FAD.
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The electron transport chain involves complexes that accept and donate electrons.
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Coenzyme Q is a non-mobile component within the lipid bilayer of the inner mitochondrial membrane.
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Molecular O2 is involved in forming H2O at the end of the electron transport chain.
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All components of the electron transport chain are small molecules.
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Pentachlorophenol is an endogenous uncoupler.
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Bilirubin at high concentrations can lead to kernicterus in infants.
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Doxorubicin inhibits Complex II of the Electron Transport Chain.
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Complex IV of the electron transport chain competes with O2 for binding sites.
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Hyperthyroidism is associated with a decrease in thyroid hormones.
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Vitamin B3 deficiency may lead to complications affecting the cardiovascular system.
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Mitochondrial diseases only arise from mutations in mitochondrial DNA.
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Aspirin overdose can lead to fever due to its function as an uncoupler.
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Electrons derived from carbohydrates, triglycerides, and proteins ultimately flow to $O_2$ in the Electron Transport Chain.
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The Electron Transport Chain takes place in the outer mitochondrial membrane.
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NADH and FADH2 are produced exclusively from the breakdown of carbohydrates.
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A proton gradient is established across the inner mitochondrial membrane during electron transport.
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The chemiosmotic theory explains ATP generation by the movement of protons through ATP synthase.
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The Electron Transport Chain (ETC) is located in the inner mitochondrial membrane.
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ATP is produced directly from NADH without the need for an electron transport chain.
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Heat generation and calcium transport are secondary functions of energy not converted to ATP in the electron transport chain.
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FADH2 and NADH are produced during glycolysis and must enter the mitochondrial matrix for ATP synthesis.
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The outer mitochondrial membrane is impermeable to small molecules.
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Uncoupling proteins can create a proton leak across the inner mitochondrial membrane.
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Brown fat uses 90% of respiratory energy for ATP production.
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Humans have abundant brown fat compared to adults.
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Thermogenin (UCP1) is responsible for heat production in brown adipose tissue.
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The total maximum ATP yield from one glucose molecule is 36 ATP in all scenarios.
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Electrons from FADH2 enter the electron transport chain at complex I.
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A proton gradient is established across the mitochondrial inner membrane during electron transport.
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Intermediates like NADH and FADH2 are produced only during the electron transport chain.
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Electrons from cytosolic NADH are transferred directly to mitochondrial NAD+ without any intermediates.
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The malate-aspartate shuttle only transfers electrons from cytosolic NADH to mitochondrial FAD.
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The electron transport chain is responsible for forming water by combining electrons with oxygen and protons.
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All components of the electron transport chain are mobile carriers capable of transferring electrons.
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NADH generated in glycolysis can directly enter the mitochondrial matrix.
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The electron transport chain is located within the outer mitochondrial membrane.
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Proton gradients established by the electron transport chain are essential for ATP synthesis.
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The energy from NADH is stored as ATP in the mitochondrial matrix.
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Study Notes
Common Disorders
- Parkinson's disease, cardiomyopathies, and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) are common disorders.
- MELAS is characterized by progressive neurodegeneration, repeated episodes of lactic acidosis and myopathy, and the presence of mutant and wild-type mtDNA in cells.
Mitochondrial Diseases
- Leber hereditary optic neuropathy (LHON) is caused by mitochondrial inheritance and affects males four times more frequently than females.
- LHON is caused by point mutations in subunits of the NADH-Q reductase, QH2 (I), cytochrome c reductase (III), or cytochrome oxidase (IV).
- LHON leads to sudden onset of blindness in young adults, typically in their 20s or 30s.
- Blindness in LHON is characterized by bilateral central vision loss caused by retinal detachment.
Oxidative Phosphorylation
- Acetyl CoA from various cellular sources enters the TCA cycle and generates reducing equivalents in the form of NADH + H+ and FADH2.
- Electrons from NADH/FADH2 are passed to the electron transport chain, with oxygen acting as the final electron acceptor.
- The transfer of electrons down the ETC is energetically favored due to NADH being a strong electron donor and O2 being an avid electron acceptor.
- As electrons pass down the chain, energy is released and used to pump H+ across the membrane, establishing a proton gradient.
- Protons move back into the mitochondrial matrix through ATP synthase, generating ATP from the energy of H+ movement.
Chemiosmotic Hypothesis
- The chemiosmotic hypothesis, also known as Mitchell hypothesis, describes how ATP is generated from the free energy released during electron transport in the ETC.
- The hypothesis involves two steps:
- Step 1: Protons are pumped from the mitochondrial matrix to the intermembranous space, creating a proton gradient.
- Step 2: The proton gradient drives ATP synthesis.
- The inner mitochondrial membrane is impermeable to protons, leading to a buildup of protons in the intermembranous space.
- The proton gradient, also known as the proton motive force, is used to drive ATP synthesis.
Electron Transport Chain (ETC)
- The ETC is the final common pathway for electrons derived from various fuels, including carbohydrates, triglycerides, and proteins.
- NADH and FADH2, produced during catabolism and the TCA cycle, donate electrons to electron carriers in the ETC.
- Electrons pass down the ETC, losing energy and generating ATP through oxidative phosphorylation (OXPHOS).
- Energy not converted to ATP is used for calcium transport and heat generation.
ETC Components
- The ETC consists of four complexes (I-IV), each accepting and donating electrons to mobile carriers (cytochrome C and CoQ).
- Mobile carriers can receive and donate electrons.
- Electrons ultimately combine with oxygen and hydrogen to form water.
- The ETC also includes freely diffusible components:
- NADH (mitochondrial matrix)
- Coenzyme Q (Ubiquinone) (mobile within lipid bilayer)
- Cytochrome C (peripheral membrane protein)
- Molecular O2
Membrane Transport of Molecules
- Specific transport systems exist for molecules like ADP and Pi, which are needed for ATP synthesis.
- ADP is transported into the mitochondria in exchange for ATP.
Substrate Shuttles
- Substrate shuttles are transport proteins that facilitate the passage of specific molecules, like NADH, from the cytosol to the mitochondrial matrix.
- The inner mitochondrial membrane lacks an NADH transport protein, necessitating shuttle systems.
- Electrons from cytosolic NADH are transferred to an intermediate, which crosses the mitochondrial membrane and then transfers the electrons back to mitochondrial NAD+ or FAD.
- Two main shuttle systems are:
- Glycerol 3-phosphate shuttle: Transfers electrons from cytosolic NADH to mitochondrial FAD.
- Malate-aspartate shuttle: Transfers electrons from cytosolic NADH to mitochondrial NAD+.
Exogenous Uncouplers
- 2,4-dinitrophenol and pentachlorophenol are examples of synthetic uncouplers
- Aspirin overdose can lead to fever due to its uncoupling properties
Endogenous Uncouplers
- Bilirubin at high concentrations can cause kernicterus (severe brain damage in infants)
- Excess free fatty acids at high concentrations can act as uncouplers
- Thyroid hormones (T3) can uncouple oxidative phosphorylation through:
- Sympathetic stimulation
- Increasing acylcarnitine production, activating mitochondrial respiration
- Directly stimulating the transcription of UCP1
Inhibition of Electron Transport Chain (ETC)
- Inhibition of any complex in the ETC leads to inhibition of ATP synthesis and cell death
- Doxorubicin inhibits at CoQ
- Rotenone (poison) inhibits Complex I
- Cyanide (CN-) and carbon monoxide (CO) inhibit Complex IV by competing with oxygen for binding
- Oligomycin binds to the Fo domain of ATP synthase, closing the H+ channel
Deficiencies Affecting ETC
- Iron deficiency inhibits any of the iron-containing complexes
- Deficiencies in vitamins B2 (Riboflavin) or B3 (Niacin) cause severe lethargy and complications in the cardiovascular, nervous, muscular, and gastrointestinal systems
- Niacin is a precursor for NAD, a coenzyme for Complex I
- Riboflavin is a precursor for FAD and FMN, its deficiency inhibits Complex I
Mitochondrial Diseases
- "Oxphos" diseases result from mutations in genes encoding proteins of the ETC complexes
- Mutations can occur in nuclear or mitochondrial DNA, therefore "mitochondrial disease" does not always exhibit "mitochondrial inheritance"
- These diseases tend to affect tissues with high energy demands, such as nervous tissue, kidney, heart, and skeletal muscle
ATP Production (Aerobic)
- Glucose complete oxidation yields a maximum of 38 ATP per molecule
- Glycolosys: 2 ATP
- Pyruvate to Acetyl CoA: 2 NADH+H+ (6 ATP)
- TCA cycle: 6 NADH+H+ (18 ATP), 2 FADH2 (4 ATP), 2 ATP
- 3 ATP per NADH+H+: Electrons from NADH enter at Complex I
- 2 ATP per FADH2: Electrons from FADH2 enter at Complex II
Uncoupling Proteins (UCP)
- Located in the inner mitochondrial membrane
- Create a proton leak, resulting in energy released as heat (non-shivering thermogenesis)
- Thermogenin (UCP1) is responsible for heat production in brown adipose tissue
- Brown fat uses 90% of respiratory energy for heat production in response to cold
- Humans have little brown fat except for neonates
Uncoupling Oxidative Phosphorylation
- Compounds that increase the permeability of the inner mitochondrial membrane uncouple oxidative phosphorylation
- No ATP synthesis occurs, and energy is released as heat
Electron Transport Chain (ETC)
- Final common pathway for electrons derived from various fuels of the body
- Electrons are passed down the chain, losing energy and generating ATP through oxidative phosphorylation
- Energy not converted to ATP is used for transporting Ca2+ and generating heat
Coenzymes
- NAD+ + 2H+ + 2e- --> NADH + H+
- FAD + 2H+ + 2e- --> FADH2
- These electrons contain a lot of energy and are "unlocked" by the electron transport chain
Mitochondria and ETC Location
- The ETC is located in the inner mitochondrial membrane
- The outer membrane is porous to small molecules
- The inner membrane is impermeable to most ions, small and large molecules
- Glycolysis takes place in the cytoplasm and produces NADH
- NADH and FADH2 need to reach the ETC complexes for ATP synthesis
- The TCA cycle occurs in the mitochondrial matrix
Membrane Transport of Molecules
- Specific transport systems for other molecules exist in the inner mitochondrial membrane
- ADP and Pi are needed for ATP synthesis
- ADP is transported in by exchanging for ATP
Substrate Shuttles
- Specific transport proteins (substrate shuttles) permit the passage of molecules from cytosol to the mitochondrial matrix
- The inner mitochondrial membrane lacks an NADH transport protein
- Only electrons from cytosolic NADH are transported into the mitochondrion by shuttle systems
Glycerol 3-phosphate Shuttle
- Electrons from cytosolic NADH are transferred to mitochondrial FAD
Malate-Aspartate Shuttle
- Electrons from cytosolic NADH are transferred to mitochondrial NAD+
ETC Components (Electron Carriers)
- All members of the ETC, except coenzyme Q, are large protein complexes
- Coupled to metal ions, such as iron and copper
- Mobile carriers (cytochrome C and CoQ) accept and donate electrons between complexes
ETC Components (Mobile Carriers)
- NADH (mitochondrial matrix)
- Coenzyme Q (Ubiquinone) - Mobile within the lipid bilayer
- Cytochrome C - Peripheral membrane protein on the outer membrane surface
- Molecular O2
ATP Synthase
- Enzyme responsible for ATP synthesis
- Uses the proton gradient generated by ETC to drive ATP production
Learning Outcomes
- Relate oxidative phosphorylation to the overall map of metabolism
- Describe the subcellular localization and organization of ETC and ATP synthase
- Discuss the chemiosmotic theory and coupling of electron transport to ATP generation
- Explain how the proton gradient drives ATP synthesis
- Explain the normal and pathophysiological outcomes of uncoupling
- Describe OxPhos diseases and how iron and vitamin deficiencies cause defects in electron transport
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Description
Test your knowledge on common mitochondrial disorders, including MELAS and Leber hereditary optic neuropathy (LHON). This quiz covers their characteristics, inheritance patterns, and effects on health. Dive into the complexities of oxidative phosphorylation and its relation to these diseases.
