Download UNIT 7 Mitochondria and hepatic detoxification

PHM142 <> UNIT 7 <> Lecture outline 2016
Mitochondrial function – TCA cycle and OXPHOS
1) Citric acid cycle as an energy source
2) The respiratory chain as an energy source
and oxidative phosphorylation
3) Discussion of:
- In a First, Aspirin Is Recommended to Fight a Form of Cancer
by Roni Caryn Rabin
- Platelet Mimicry, by Omid C. Farokhzad
- Nanoparticle Biointerfacing by Platelet Membrane Cloaking by C-M. J. Hu
et al., 2015
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Compartmentalization
of the major pathways
of metabolism
Inner membrane:
Oxidative phosphorylation
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The link btw.
glycolysis
and the TCA
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The CAC (TCA) is the 1st stage in cellular respiration – removal
of high E electrons from carbon fuels (left). These electrons
reduce O2 to generate the proton gradient (red pathway) which
is used to syn. ATP.
<> The reduction of O2 and the syn. of ATP constitute Ox Phos.
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THE CITRIC ACID CYCLE IS A SOURCE OF
BIOSYNTHETIC PRECURSORS
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THE MITOCHONRIAL
RESPIRATORY CHAIN AS AN
ENERGY SOURCE
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Origin of mitochondria: the endosymbiont hypothesis
The endosymbiont hypothesis suggests that mitochondria have evolved
from anaerobic bacteria which were phagocytosed by eukaryote cells
at the time oxygen appeared on earth,
Similarities between mitochondria and bacteria include the presence of:
• cardiolipin
•transporters
• ribosomes
• circular RNA and DNA
Therefore mitochondria protein synthesis can be inhibited by:
• TETRACYCLINE
• CHLORAMPHENICOL.
E.g. The extensive use of these drugs can inhibit
1. Bone marrow mitochondrial protein synthesis leading to a
decline in the production of white or red cells.
2. Intestinal epithelial cells causing them to cease dividing.
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The mitochondrial respiratory chain
NADH
Diagram of a mitochondrion
FMNH2
complex I
NADH-Q
reductase
Q
2Fe-2S
4Fe-4S
FADH2
in flavoproteins
succinate:Q reductase
(complex II)
complex III Cytochrome
reductase
Chemiosmotic theory of oxidative phosphorylation
cyt c
complex IV Cytochrome
oxidase
O2
Sequence of electron
carriers in the
respiratory chain
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Oxidative phosphorylation
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NADH coenzyme Q reductase: complex I
FMN
NADH
NAD+
Q
Reduced Fe-S
FMNH2
Oxidised Fe-S
QH2
NADH-Q reductase
O
H3 CO
C
H3 CO
C
C
C
O
C
CH3
CH3
C
(CH2C
H
C
O
Coenzyme Q10
(UBIQUINONE
e- + H+
CH2 )10
H
H3 CO
C
H3 CO
C
C
C
OH
e- + H+
C
CH3
H3 CO
C
C
R
H3 CO
C
OH
Semiquinone
Intermediate
(Q )
C
C
C
CH3
C
R
OH
Reduced Coenzyme Q10
( UBIQUINOL)
The reduction of ubiquinone to ubiquinol proceeds through a semiquinone
anion intermediate.
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Cytochrome oxidase (Complex IV)
Lodish Fig. 17-30
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Cytochrome C – soluble, NOT membrane bound protein
1. 26/104 amino acids residues have been invariant for 1.5 x 109 years.
2. Met 80 and His 18 - coordinate Fe.
3. 11 residues from number 70 - 80 lining a hydrophobic crevice have
remained virtually unchanged throughout all cytochrome c regardless
of species or even kingdom.
4. A number of invariant arginine and lysine clusters can be found on
the surface of the molecule.
Cytochrome c has a dual function in the cell. Electron transport for ATP
production AND the major cause of most programmed cell death
(apoptosis) is initiated by the release of cytochrome c into the cytosol!
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Cytochrome C - catalytic site
R C
CH2
H
Vinyl group
of the heme
+
HS C
R'
H2
Cysteine
residue
of the protein
CH3
R C
S C
R'
H
H2
Thioether linkage
The cytochromes are iron-containing
electron transfer proteins of the
mitochondrial inner membrane.
The iron atom of the heme group in
cytochrome c is bonded to a sulfur atom in
the cysteine side chain and a
histidine nitrogen atom.
The heme in cytochromes c and c1 is
covalently attached to 2 cysteine side chains
by thioether linkages.
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Electron transport can be
blocked by specific inhibitor
poisons
NADH
NADH-Q
Reductase
QH2
Blocked by
rotenone and
amytal
Cytochrome b
Blocked by
antimycin
Cytochrome c1
Sites of action of some
inhibitors of electron
transport
Cytochrome c
Cytochrome Oxidase
Blocked by
CN- , N3 -, and CO
O2
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Discussion of:
In a First, Aspirin Is Recommended to Fight a Form of Cancer
by R. C. Rabin
Discussion of strategies and details of:
Nanoparticle Biointerfacing by Platelet Membrane Cloaking
By C-M. J. Hu et al., 2015
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