ETC Flashcards
ETC overview
- energy rich molecules are metabolized by series of oxidation reactions yielding CO2 and H2O
- oxidation reactions are coupled to the transfer or electrons(reduction) to the electron carriers FAD and NAD+(oxidation)
- carriers donate electron to ETC and lose free eneegy
- electron is coupled with proton to create gradient
- flow of protons drives ATP synthase
RedOx chemical reactions
-represent transfer of H atoms (1 proton and 1 electron)
Mitochondria outer membrane
-permeable to most ions and small molecules
Mitochondria inner membrane
-impermeable to most small ions and small and large molecules
Mitochondrial matrix
- TCA cycle enzymes (except complex 2)
- fatty acid oxidation enzymes
- mtDNA and mtRNA (circular and encode for some things involved in ETC)
- mitochondrial ribosomes
- ETC takes place here
protein complexes
- embedded in the inner membrane and span the WHOLE membrane.
- complexes 1-4 are part of the electron transprt
- complex 5 is the enzyme ATP-synthase
- CoQ is the only nonprotein carrier (hydrophobic and can freely move around the membrane)
Complex 1
- NADH dehydrogenase
- accepts electron from NADH generated during glycolysis, pyruvate decarboxylation, and TCA cycle
- contains FMN that accepts 2 hydrogen atoms
- contains iron sulfur center required for next step
Complex 2
- succinate dehydrogenase
- ONLY ONE embedded in inner mitochondrial membrane
- FAD contains iron sulfur center
- FADH2 generated are directly transferred to CoQ and skip complex 1
Coenzyme Q
- only non protein carrier
- quinine derivative with long hydrophobic tail so it can freely move along membrane
- accepts the electron from complex 1 and 2 and pass them to complex 3
Cytochrome proteins
- CYT
- Cyt b and c1=complex 3
- Cyt a and a3=complex 4
- Cyt c freely moves in intermembrane space because soluble
- each contain heme group
- Cyt iron is reversibly converted from ferric(Fe3+) to ferrous(Fe2+)
Complex 4
- Cyt a and a3 or c oxidase
- contains copper required for electron transfer
- the only complex that contains heme iron group that directly interacts with O2
- electron moves from CuA to Cyta3 associated with Cub to O2
- oxygen is last acceptor because it is the strongest
Strongest donor and acceptor
- NADH is strongest donor
- O2 is strongest acceptor so held for last so you can continue to transfer electrons down the chain
Chemiosmotic hypothesis
- as electrons go through 1,3,4, the reaction is coupled with pumping of protons across inner mitochondrial membrane to intermembrane space
- creates electrical and pH gradient(outside is more positive)
- gradient drives ATP synthesis
- gradient serves as common intermediate that couples oxidation to phosphorylation
Complex 5
- ATP-Synthase
- multisubunit enzyme
- domain F0-spans mitochondrial membrane
- domain F1- is extramembranous(in mitochondrial matrix)(head spear is in matrix)
ATP-Synthase Function
- protons flow back through F0 domain driven by the gradient
- F1 domain rotates
- F1 goes through conformational changes that allow ATP+P to bind and phosphorylate ADP—>ADP, and release ATP
Inhibition of ETC
- prevent the flow of electrons
- results in NADH build up
- build up inhibits TCA cycle and causes pyruvate to go to lactate
- serum lactate levels elevate
- highly aerobic tissues are effected(heart and brain)
-any inhibition will stop the whole damn thing
Inhibition of Complex 1
Amytal- a barbiturate, okay to take medication if correct dosage
Rotenone- insecticide, piscicide, and pesticide
Inhibition of Complex 3
Antimycin A(piscicide
CN Inhibition of Complex 4
Cyanide-irreversibly binds to ferric in the heme group of Cyt C-oxidase
-seen in people exposed to fires
CO inhibition of Complex 4
-binds reversibly however the primary toxicity is associated with tight binding to hemoglobin
NaN3 inhibition of Complex 4
- binds to ferris in cytochromes
- used as propellant in air bags and explosives
- used as antimicrobial preservatives
Inhibition of Complex 5
Oligomycin- binds fo F0 domain and closes the proton channel leading back to the matrix and shuts down ATP synthesis
-used to study ETC in labs
Coupling in normal mitochondria
- ATO synthesis is coupled to electron transport through the proton grandient
- change in one has the same effect on the other
Uncoupling
-allowing protons to flow back through the membrane without generation of ATP
Natural- UCP’s localized in mitochondrial membrane (creates protein leak)
Synthetic- non protein compounds that increase permeability of the inner mitochondrial membrane to protons
Uncoupling proteins
-allow proton to go back to the matrix by skipping complex 5 and not generating ATP
Nonshivering thermogenesis
-free energy released as heat by UCP
UCP1
- thermogin
- found in brown fat
UCP2,3,4,5
- have been found in other tissues(heart, muscle, liver) but their function is not known
- tissue specific
2,4-dinitrophenol
- weight loss in 1930
- easy to overdose
- fatal hypothermia
Salicylic acid
- can cause uncoupling
- aspirin
- high fever/sweating/fatal overdose
Reactive oxygen species
- incomplete reduction of oxygen to water causes production of ROS
- O2-, H2O2, OH radicals
- unavoidable product of ETC
- potential to damage things in mitochondria
- damage/mutations in ETC components can increase production of free radicals
mtDNA
- encodes 13 of 120 proteins required for oxidative phosphorylation
- high mutation rate due to ROS
- mutations of oxidative phosphorylation highly affect aerobic tissues
Apoptosis
- programmed cell death
- initiated through mitochondrial intrinsic pathways resulting in the formation of pores in the outer membrane
- pores allow Cyt c to be released into the cytosol
- Cyt-c can interact and activate proteolytic enzymes(caspases)
- caspases cause cleavage of proteins that change characteristics and result in apoptosis
Iron level deficiency
- several proteins in ETC require Iron
- low levels may result in tiredness and iron deficiency anemia
LHON
- leber hereditary optic neuropathy
- optic neuropathy and optic atrophy
NARP
- Neruological muscle weakness, Ataxia, Retinitis pigmentosa
- retinal dystrophy, cone dystrophy
MILS
- Maternally inherited Leigh disease
- RPE dystrophy, optic atrophy
MELAS
- Mitochondrial encephalopathy, lactic acidosis, stroke like episodes
- Maculopathy, cone-rod dystrophy, hemianopsia
MIDD
Maternally inherited diabetes and deafness
-Pattern maculopathy, pigmentary retinopathy
MERRF
Myoclonic epilepsy, ragged red fibers
-optic atrophy, mild pigmentary retinopathy
KSS
Kearns-sayre Syndrome
-Pigmetary retinopathy, strabismus ptosis
CPEO
chronic progressive extraocular ophthalmoplegia
-ptosis, strabismus, ophthalmoplegia
