UNIVERSITY Of JORDAN

Faculty OF Medicine

LECfURE NO: 11

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"'1---1 DONE BY: Nrld Haddad

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 • In this lecture we ullk about certain inhibilO~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 A TP 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

IV

- 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) Uncoupl~rs: Chemical uncouplers indud~:

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 pre~nt 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

substances.

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
pyruvate.

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

~cytosol"
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~mbrane 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.

NOTES;

1. In mlllillte--aspartate sbuttle, reserving energy in the form ofNADH.

resuhs in J ATP molecules:

NADH (cystol) + NAD+ ( mll1 riw) ~ NADt (crystal)+­

NADH(matrix)

2. In Gly«rol ]- phosphite ,fl.ttle, FADH2 results in 2 ATP

molecules, that's why oxidative phosphorylation generales (36-38) ATP
molecules.

5
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

gluterate.

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THE END

Done by
Nael baddad