Faculty OF Medicine
_'_OO_8 -.J1
"'1---1 DONE BY: Nrld Haddad
"-_--I DR.: Nfl!!! KnnJl{,Il/i,.h
• In this lecture we ullk about certain i n h i b i l O ~ t disorders and how
metabolites enter the inner mitochondrial membrane.
• Energy utilization:
As we ean see from lIle figure in the slides that 90-95% of the inhaled
oltygen is consumed by the mitochondria. The remaining 0lCYgen (5­
10%) is used by a group of enzymes called Oxidases including Mono
Oxygenases,Di Oxygenases which we will sLUdy later during the course.
• A large portion of the energy produced is coupled to ATP synthesis.
Some of the energy dissipates without A1P synthesis. This encrgy is
produced in thc form of heat
ATP produced can be used for a variety of cellular activities such as:
prolein synthesis. sodiumlpotassiwn ATPase and muscle contraction.
More cltamplcs are found in the slide.
• Respiratory chain inhibitors:
These substances block the electron transport chain. All components of
the electron Inll1SJXlrt chain before the block are reduced while
components after lIle block are oxidized.
-EJWmples on these inhibitors:
I) lnhibilors of electron flow:
a) Amytal & Rotenone: They aet on complex I
b) Antimycin A: Acts on complex III
c) Cyanide. carbon monox..ide and sodiwn azide: They aet on complex
- Cyanide is a very powerful inhibitor. This makes i! cxtremely
da.ngerous and lethal. CylUlide can also bind to haemoglobin.
2) Oligomycin: Binds tu the Fo ponion. It causes the blockage of
protons. Phosphorylation slopS and prolOrts will be kept in the
intennembrane space.
3) Chemical uncouplers
a) 2.4-DNP (Oi Nitro Phenol): it allows proton5 to re enter the inncr
mitochondrial membrane. so energy is released in the form of heat and
nol being captured as ATP.
b) Arsenale: It acts as a substitute for phosphate during ATP
synthesis. So instead of binding of phosphate group to ATP, arsenate
binds to il.

- Arsenate: HAs04

-Arsenite (trivalent) As02: binds IxIth ofthe -SH groups of the co
factor lipoic acid. It is considered more toxic.
4) Atraetyloside: It causes the blockage of the ATP/ADP antiponer (il
is one type oflranspon proleins found in the inner mitochondrial
membrane. it transpons ATP outside the membrane and ADP inside).
• Natural Uncoupling Proteins (UCP):
- Uncoupling proteins create a proton leak allowing protons to re enler
the mitochondrial matrix which result in the production ofenergy in the
form of heat.
- These proteins are foWld in the inner membmne of the mitoChondria.
• Types or Uncoupling Proteins:
a) UCPI (Thennogenin): Found in brown fat. Brown fat is found in
newly born babies. and animals espedtdly the hibemating..animals.
"Production of heat in response to cold".
b) UCP2: Found in most cells.
c) UCP3: Found in skeletal muscles.
d) UCP 4 & UCP5: Found in the brain.
• Uncoupling proteins nre p r e ~ n t in small amounts in the human adults.
• Aspirin. which is used tor relieving pain and reduction of fever, Clln act
as uncoupling proteins under high doses. This explains the high fever
whieh accompanies the overdose of aspirin.
• Inherited defects in oxidative phosphorylation:
- 13 of the approximately 100 polypeptides required for oxidative
phosphorylation are coded for by milochondrial DNA.
- Defects in oxidative phOSphorylation an: more likely to be as a result of
alterations in mitochondrial DNA, since it has a mutation rate 10 times
greater than that of nuclear DNA.
• We said above that 13 afme polypeptides are coded by mitochondrial
DNA. They are distributed as the following:
A) One in complex nI.
B) Three in complex IV.
C) Seven in complex L
D) Two in Fo.
• Mitochondrial DNA is maternally inheriled because mitochondrion
from the sperm does not enter the fertilized egg.
- These disorders indude:
1) Mitochondrial myopathies.
2) Leber's heredilary tlptic neuropathy: defect in the NADH
Dehydrogenase polypeptide.
• Transpon systems afthe inner mitochondrial membnmo::
• The outer membrane of lhe mitochondria is highly ptnno:able to many
1) Antipon (most common): 1bey are transpon proteins which exchange
2 molC(u!es of similar charges. Example: ATP/ADP antiport... ATP out·
ADP in.
2) Sympon: Co transporting of2 molecules of opposite charges.
Example: proton co transponing phosphale & proton co transponing
3) Calcium ion unipon protein: No other ions are involved. calcium ions
(positive) move from a positive region to a negative region. (See figure in
the slides).
• NAD+ mulecules are reduced either in "milOChondrial matrix" or
~ c y t o s o l "
Those of which reduced in the cytosol require a special shuttle to get a
way inside the mitochondria, because the inner mitochondrial membrnne
is irnpenneable to NADH. and no transport protein exists that can
direi::tly trunslocate NADH across this membrane.
• There are two alternate shuttles for NADH translocation:
A) The Malate.Aspartate Shuttle:
• Mechanism:
I) NADR(cytosol) mluees Oxaloacetate (OM) 10 malate.

2) Malate crosses the inner mitothondrial membrane. and then reoxidized
to (OAA).
• This step regenerates NADH, and reserves energy.
- (OAA) can't cross the mcmbrnne, so it's converted to aspartate.
J) Aspartate crosses the inner m ~ m b r a n e back to the cytosol.
4) To complete the cycle. aspartate is converted back to (OAA).
B) The Glyceropbosphau: Shuttle:
1) Dihydroxyace1one-p (DHAP) is reduced to glycerol-J-p, using
eytosolic glycerol.3.p dehydrogenase.
2) Glycerol-3-p reaches the inner membrane, then become oxidized
reducing FAD to FADII.
3) (DHAP) goes back to cytosol.
1. In mlllillte--aspartate sbuttle, reserving energy in the form ofNADH.
resuhs in J ATP molecules:
NADH (cystol) + NAD+ (
riw) ~ NADt (crystal)+­
2. In Gly«rol ]- phosphite ,fl.ttle, FADH2 results in 2 ATP
molecules, that's why oxidative phosphorylation generales (36-38) ATP
3. When w ~ remove an amino group from aspartate we get o,>taloacetatc.
4. When we remove an amino group from glutamate we get alpha-keto
<;<;<;<;<;«««««-:CllECK 1HE DOCTOR"S SlIDt:S»»»»»»»»»>
Done by
Nael baddad