ETC Flashcards
ETC overview
the oxidation reactions are coupled to the transfer of e- (reduction) to the e- carriers NAD+ and FAD (oxidized)
redox reactions in biological systems
represent transfer of H atoms
mitochondria: outer membrane
permeabel to most ions and small molecules via small channels, porins
mitochondria: inner membrane
impermeabel to most small ions, small and large molecules
mitochondria: matrix
- TCA cycle enzymes
- FA oxidation enzymes
- mtDNA and mtRNA
- mitochondrial ribosomes
mitochondria
transcriptional and translational machinery
complexes imbedded in the inner membrane
complexes I, II, III, IV, V
-spans the whole membrane from side to side
Complex V
enzyme ATP-synthase
What is the only nonprotein carrier?
CoQ
complex I
- NADH dehydrogenase
- accepts e- from glycolysis, TCA
- FMN, accepts H atoms to make FMNH2
- iron sulfur center
complx II
- succinate dehydrogenase
- the only TCA enzyme embedded in the inner mitochondrial membrane
- FAD contains iron sulfur center
CoQ
- ONLY nonprotein carrier
- quinine derivative with long hydrophobic tail
Complex III
- cyt b
- cty c1
complex IV
- cyt a
- cyt a3
cyt c
freely moving in the inter membrane space
Cyt iron
reversibly converted from ferric (Fe3+) to ferrous (Fe2+) form
Complex IV
- cyt a+a3 or cytochrome c oxidase
- Cu required for e- transport
- only complex in which the heme Fe has a site that directly reacts with O2
- e- moves from Cua to Cyt a3
Transfer of e- down the ETC
driven because NADH is a strong electron do not, and O2 is a strong electron acceptor
oxidative phosphorylation: the chemiosmotic hypothesis
- electrical gradient
- pH gradient
- this energy created by this used to drive ATP synthesis
- proton gradient serves as common intermediate that couples oxidation to phosphorylation
Complex V
- ATP-synthase
- multisubunit enzyme
- domain Fo spans the inner mitochondrial membrane
- domain F1-extramembranous that appears as a sphere that protrudes into the matrix
ATP-synthase function
- protons flow back through Fo, driven by gradient, which drives rotation of F1 domain
- rotation of F1 causes conformational change that allow it to bind ATP +Pi, and phosphorylate ADP to ATP and release ATP
inhibition of ETC
- blocking e- transfer by any one of these inhibitors stops electron flow from substrate to O2 because the reactions of ETC are tightly coupled like meshed gears
- lactate build up, highly aerobic tissues affected
Complex 1 inhibitor: amytal
- barbiturate
- proper drug usage
Complex I inhibitor: rotenon
used as an insecticide, piscicide, and pesticide
Complex III inhibitor: antimycin A
piscicide
Complex IV inhibitor: cyanide (CN-)
- irreversibly binds to the Fe3+ in the heme group of Cyt C-oxidase
- house fires
Complex IV inhibitor: CO2
-binds irreversibly however the primary toxicity is associated with the tight binding to hemoglobin
Complex IV inhibitor: sodium azide (NaN3)
-binds similarly to cyanide to the Fe3+ of iron in cytochrome. propellant in airbags, explosives, in lab as antimicrobial perservative
Complex V inhibitor: Oligomycin
binds to the Fo domain closing the proton channel leading back into the matrix, shutting down ATP synthesis. a tool to study ATP in the lab
coupling in normal mitochondria
ATP synthesis is coupled to e- transport through the H+ gradient
uncoupling
allowing the H+ to flow back through the membrane without generation of ATP
uncoupling: naturally
UCPs localized in the inner mitochondrial membrane
synthetic uncouplers
nonprotein compounds that increase he permeability of the inner mitochondrial membrane to H+
UCPs
- allow H+ to flow back into matrix
- free energy released as heat (non shivering thermogenesis)
UCP1 (thermogenin)
found in brown adipose tissue of mammals
UCP2, 3, 4, and 5
found in other tissues but function not understood
2,4-dinitrophenol
- synthetic uncoupler
- weight loss drug
- fatal hyperthermia
salicylic acid
- causes uncoupling
- aspirin
- overdoses will cause high fever, profuse sweating, and can be fatal
Reactive Oxygen Species (ROS)
- unavoidable by product of ETC
- incomplete reduction of oxygen to water
- can damage proteins, lipids, DNA, RNA, etc, present in mitochondria
- can increase production of free radicals
mtDNA
- encodes 12 of 120 proteins
- constant exposure to ROS
- oxidative defects in oxidative phosphorylation
- severly affect highly aerobic tissues
Leber Hereditary Optic Neuropathy (LHON)
MERRF, and MELAS. Leigh syndrome can result from mutations in tDNA or nuclear DNA
mitochondrial in apoptosis
- intrinsic
- pores
- allow Cyt C to be released
- caspases (proteolytic enzymes)
- cause cleavage of key proteins
iron deficiency
- several proteins in the ETC require iron
- tiredness
Leber hereditary optic neuropathy (LHON)
optic neuropathy
optic atrophy
Neurogenic muscle weakenss ataxia retinitis pigmentosa (NARP)
retinal dystrophy
cone or cone-rod dystrophy
Maternally inherited Leigh disease (MILS)
RPE dystrophy
Optic Atrophy
Mitochondrial encephalopathy lactic acidosis stroke like episodes (MELAS)
maculopathy
Cone-Rod dystrophy
Hemianopsia
Maternally inherited diabetes and deafness (MIDD)
pattern maculopathy
pigmentary retinopathy
Myoclonic epilepsy ragged red fibers (MERRF)
Optic atrophy
Mild pigmentary retinopathy
Kearns-Sayre Syndrome (KSS)
Pigmentary retinopathy
strabismus ptosis
Chronic progressive extraocular ophthalmoplegia (CPEO)
Ptosis
Strabismus
Ophthalmoplegia
