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OXIDATIVE PHOSPHORYLATION
Dr. Ashok Kumar JInternational Medical School
Management and Science UniversityMalaysia
Dr. Ashok Kumar J; Professor; Biochemistry
Oxidation is defined as the removal of electrons
Reduction as the gain of electrons
Oxidation is always accompanied by reduction of an electron acceptor
Fe2+ Fe3+
e- (Electron)
Cu+ Cu2+
e- (Electron)
Fe2+ + Cu2+ Fe3+ + Cu+
Dr. Ashok Kumar J; Professor; Biochemistry
Entire process is known as cell respiration
OXIDATION OF METABOLIC FUELS IS ESSENTIAL TO LIFE
Higher organisms dietary fuels are metabolized to:1. Carbon dioxide (CO2 ; Fully oxidized form of carbon) 2. Water fully reduced form of oxygen
Fuels
Oxidized
Electrons are transferred to
coenzymesETC
ATPADP
CO2
½ O2
H2O
Dr. Ashok Kumar J; Professor; Biochemistry
Glycolysis
Cytoplasm
Pyruvic acid
Krebs Cycle
Electrons carried in NADH and FADH2
Electron Transport
Chain
Mitochondrion
Substrate level phosphorylation Oxidative phosphorylation
Dr. Ashok Kumar J; Professor; Biochemistry
ELECTRON TRANSPORT CHAIN
Dr. Ashok Kumar J; Professor; Biochemistry
Matrix
A Cell
One of ItsMitochondria
A Crista
Outer& InnerMembranes
IntermembraneCompartment
MITOCHONDRIA
Dr. Ashok Kumar J; Professor; Biochemistry
ELECTRON TRANSPORT CHAINThere are four different complexes
Complex I, II, III, IV,
Dr. Ashok Kumar J; Professor; Biochemistry
Dr. Ashok Kumar J; Professor; Biochemistry
Peter D. Mitchell
United KingdomGlynn Research Laboratories Bodmin, United Kingdom
b. 1920d. 1992
Mitchell’s hypothesis explains Mechanism of Oxidative
phosphorylation
Dr. Ashok Kumar J; Professor; Biochemistry
Energy from oxidation of components in the respiratory chain is coupled to the translocation of hydrogen ions (protons, H+) from the inside to the outside of the inner mitochondrial membrane.
Complexes I, III, and IV acts as a proton pump
Mitchell’s chemiosmotic theory
Dr. Ashok Kumar J; Professor; Biochemistry
Complex I and complex III pumps 4 protons each
Complex IV pumps 2 protons To inter-membranous space
10 protons are pumped by the electron transport chain
The transfer of two electrons from NADH+ H+ to O2 is
accompanied by the outward pumping of 10 H+
10 protons are pumped out per NADH 1. 4 must flow in to produce 1 ATP2. The proton-based P/O ratio is 2.5 for NADH as the electron donor and 1.5
(6/4) for succinate
Dr. Ashok Kumar J; Professor; Biochemistry
ATP synthase
1. ATP Synthesizing enzyme complex2. Two major components (F0 and F1)3. F1 in all aerobic organisms consists of
- α3β3γδε subunits- binding sites for ATP and
ADP- Catalytic site for ATP
synthesis
Dr. Ashok Kumar J; Professor; Biochemistry
P:O Ratio
Number of moles of inorganic phosphate consumed per atom of oxygen utilized
Phosphate group esterifiedP:O ratio =
Electron pairs transferred
Number of moles of inorganic phosphate consumed per atom of oxygen utilized
Dr. Ashok Kumar J; Professor; Biochemistry
Paul Boyer (1964) proposed that a conformational change in the mitochondrial membrane protein leads to synthesis of ATP
Paul Boyer hypothesis is now considered as- rotatory motor- engine driving model- binding change model
To explain generation of ATP
Dr. Ashok Kumar J; Professor; Biochemistry
In response to proton influx ‘γ’ subunit physically rotates
This induces conformational change in the β3 subunit
β Subunit can adopt different conformationsLoose (L) conformation - (ADP and Pi bind )Tight (T) conformation - (Tightly bound ATP) Open (O) conformation - (Release ATP)
[ATP]
Dr. Ashok Kumar J; Professor; Biochemistry
[ADP] [Pi]
[NADH][NAD+]
Increases rate of mitochondrial respiration
Enhanced oxidative phosphorylation
Increased ATP synthesis
Cellular activityATP is used
ADP concentration increased
Increased rate of catabolism of nutrients
Mitochondrial ADP concentration has important role in
regulating oxidative phosphorylation
RESPIRATORY CONTROL
ADP transport across the inner mitochondrial membrane can be inhibited by Atractyloside
It can inhibit oxidative phosphorylation
Dr. Ashok Kumar J; Professor; Biochemistry
UncouplersUncouplers is to dissociate oxidation in the respiratory chain from phosphorylation
Compounds are toxic in vivo, causing respiration to become uncontrolled, since the rate is no longer limited by the concentration of ADP or Pi
Uncouplers2,4 dinitro phenolDinitrocresolPentachlorophenolCCCP (m-chlorocarbonyl- cyanide phenyl hydrazine)
Dr. Ashok Kumar J; Professor; Biochemistry
Physiological uncouplersThyroxineLong chain free fattyacidsUnconjugated bilirubin
IonohoresValenomycin (Ionophore for K+ ions)Nigercin (Ionophore for K+ ions)
Electron transport chain continues; energy is released as heat
Dr. Ashok Kumar J; Professor; Biochemistry
Brown adipose tissue
Characterized by- High content of mitochondria- High content of cytochrome- Well developed blood supply- Relatively rich in carnitine- Has low ATP synthase activity- High oxygen consumption- Involved mainly in metabolism particularly at times when
heat generation is required
Brown color is due to relatively high content of mitochondria
Dr. Ashok Kumar J; Professor; Biochemistry
Tissue is extremely active in In some species in arousal from hibernationIn animals exposed to cold (non-shivering thermogenesis)In heat production in the newborn animal
• Shown to be active in normal individuals • Responsible for diet induced thermogenesis
‘Eat and do not get fat
Dr. Ashok Kumar J; Professor; Biochemistry
Disorders of mitochondrial function• About 100 polypeptides are required for oxidative phosphorylation
• 13 of these polypeptides are coded by mitochondrial DNA (mtDNA) and synthesized in the mitochondria
Mitochondrial is maternally inherited(Mitochondria from the sperm do not enter the fertilized ovum)
Mitochondrial DNA is about 10 times more susceptible to mutations than nuclear DNA
Dr. Ashok Kumar J; Professor; Biochemistry
Characterized by - Accumulation of lactic acid- Myopathies- Cardiomyopathies- Encephalopathies
Mitochondrial Myopathies
• Characterized by the presence of mitochondria with abnormal shape and size• Typically results in muscle fibers appearing as ragged red fibers
( Muscle biopsy; Gomori trichrome or other stains)
May result in cell deathParticularly affect skeletal and cardiac muscles
Courtesy of Dr Ana Sotrel
Gomori trichrome stain. Mitochondrial myopathy.
There are several isolated muscle fibers with red granular staining and
disruption of fiber structure.
A. MRI of the brain showing atrophy and enhancing low attenuation
lesions. B. B. Gomori trichrome stain showing
a ragged red fiber (black arrow) and two severely atrophic denervated
fibers (white arrow).
Mitochondrial encephalomyopathy lactic acidosis stroke like episodes (MELAS)
- Complex I defect; Lactic acidosis, strokes,myopathy,seizures, dementia
Leber's hereditary optic myopathy (LHON) • Characterized by blindness in young males• Caused by a single base mutation in NADH Coenzyme Q
reductase• Streptomycin induced deafness is also found to be due to a
mutation in the mitochondrial rRNA
Myoclonic epilepsy ragged red fiber disease (MERRF)• Myoclonic epilepsy, myopathy, dementia
Leigh's syndrome• Complex I defect; Movement disorders
Dr. Ashok Kumar J; Professor; Biochemistry
THANK YOU