Cellular Respiration 

Index to this page

Mitochondria
 The Citric Acid Cycle
Cellular respiration is the process of oxidizing food
molecules, like glucose, to carbon dioxide and  The Electron Transport Chain
water. The energy released is trapped in the form of  Chemiosmosis in Mitochondria
ATP for use by all the energy-consuming activities  How many ATPs?
of the cell.  Mitochondrial DNA (mtDNA)

The process occurs in two phases:

 glycolysis, the breakdown of glucose to pyruvic acid

 the complete oxidation of pyruvic acid to carbon dioxide and water

In eukaryotes, glycolysis occurs in the cytosol. (Link to a discussion of glycolysis). The

remaining processes take place in mitochondria.

Mitochondria
Mitochondria are membrane-enclosed organelles distributed through the cytosol of most
eukaryotic cells. Their number within the cell ranges from a few hundred to, in very active cells,
thousands. Their main function is the conversion of the potential energy of food molecules into
ATP. Mitochondria have:

 an outer membrane that encloses the entire structure

 an inner membrane that encloses a fluid-filled matrix
 between the two is the intermembrane space
 the inner membrane is elaborately folded with shelflike
cristae projecting into the matrix.
 a small number (some 5–10) circular molecules of DNA

This electron micrograph (courtesy of

Keith R. Porter) shows a single
mitochondrion from a bat pancreas cell.
Note the double membrane and the way the
inner membrane is folded into cristae. The
dark, membrane-bounded objects above the
mitochondrion are lysosomes.

The number of mitochondria in a cell can

  increase by their fission (e.g. following mitosis);
 decrease by their fusing together.

(Defects in either process can produce serious, even fatal, illness.)

The Outer Membrane

The outer membrane contains many complexes of integral membrane proteins that form channels
through which a variety of molecules and ions move in and out of the mitochondrion.

The Inner Membrane

The inner membrane contains 5 complexes of integral membrane proteins:

 NADH dehydrogenase (Complex I)

 succinate dehydrogenase (Complex II)
 cytochrome c reductase (Complex III; also known as the cytochrome b-c1 complex)
 cytochrome c oxidase (Complex IV)
 ATP synthase (Complex V)

The Matrix

The matrix contains a complex mixture of soluble enzymes that catalyze the respiration of
pyruvic acid and other small organic molecules.

Here pyruvic acid is

 oxidized by NAD+
producing NADH + H+
 decarboxylated producing
a molecule of
o carbon dioxide
(CO2) and
o a 2-carbon
fragment of
acetate bound to
coenzyme A
forming acetyl-
CoA

The Citric Acid

Cycle
  This 2-carbon fragment is donated to a molecule of oxaloacetic acid.
 The resulting molecule of citric acid (which gives its name to the process) undergoes the
series of enzymatic steps shown in the diagram.
 The final step regenerates a molecule of oxaloacetic acid and the cycle is ready to turn
again.

Summary:

 Each of the 3 carbon atoms present in the pyruvate that entered the mitochondrion leaves
as a molecule of carbon dioxide (CO2).
 At 4 steps, a pair of electrons (2e-) is removed and transferred to NAD+ reducing it to
NADH + H+.
 At one step, a pair of electrons is removed from succinic acid and reduces FAD to
FADH2.

The electrons of NADH and FADH2 are transferred to the electron transport chain.

The Electron Transport Chain

The electron transport chain consists of 3 complexes of
integral membrane proteins

 the NADH dehydrogenase complex (I)

 the cytochrome c reductase complex (III)
 the cytochrome c oxidase complex (IV)

and two freely-diffusible molecules

 ubiquinone
 cytochrome c

that shuttle electrons from one complex to the next.

The electron transport chain accomplishes:

 the stepwise transfer of electrons from NADH (and

FADH2) to oxygen molecules to form (with the aid of
protons) water molecules (H2O);

(Cytochrome c can only transfer one electron at a

time, so cytochrome c oxidase must wait until it has
accumulated 4 of them before it can react with
oxygen.)
  harnessing the energy released by this transfer to the pumping of protons (H+) from the
matrix to the intermembrane space.
 Approximately 20 protons are pumped into the intermembrane space as the 4 electrons
needed to reduce oxygen to water pass through the respiratory chain.
 The gradient of protons formed across the inner membrane by this process of active
transport forms a miniature battery.
 The protons can flow back down this gradient, reentering the matrix, only through
another complex of integral proteins in the inner membrane, the ATP synthase complex
(as we shall now see).

Chemiosmosis in mitochondria
The energy released as electrons pass down the gradient from NADH to oxygen is harnessed by
three enzyme complexes of the respiratory chain (I, III, and IV) to pump protons (H+) against
their concentration gradient from the matrix of the mitochondrion into the intermembrane
space (an example of active transport).

As their concentration increases there (which is the same as saying that the pH decreases), a
strong diffusion gradient is set up. The only exit for these protons is through the ATP synthase
complex. As in chloroplasts, the energy released as these protons flow down their gradient is
harnessed to the synthesis of ATP. The process is called chemiosmosis and is an example of
facilitated diffusion.

One-half of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E.
Walker for their discovery of how ATP synthase works. Link to some of the details.

External Link
Animations of the electron transport chain and the workings of ATP synthase
Please let me know by e-mail if you find a broken link in my pages.)

How many ATPs?

It is tempting to try to view the synthesis of ATP as a simple matter of stoichiometry (the fixed
ratios of reactants to products in a chemical reaction). But (with 3 exceptions) it is not.

Most of the ATP is generated by the proton gradient that develops across the inner mitochondrial
membrane. The number of protons pumped out as electrons drop from NADH through the
respiratory chain to oxygen is theoretically large enough to generate, as they return through ATP
synthase, 3 ATPs per electron pair (but only 2 ATPs for each pair donated by FADH2).

With 12 pairs of electrons removed from each glucose molecule,

 10 by NAD+ (so 10x3=30); and

 2 by FADH2 (so 2x2=4),

this could generate 34 ATPs.

Add to this the 4 ATPs that are generated by the 3 exceptions and one arrives at 38.

But

 The energy stored in the proton gradient is also used for the active transport of several
molecules and ions through the inner mitochondrial membrane into the matrix.
 NADH is also used as reducing agent for many cellular reactions.

So the actual yield of ATP as mitochondria respire varies with conditions. It probably seldom
exceeds 30.

The three exceptions

A stoichiometric production of ATP does occur at:

 one step in the citric acid cycle yielding 2 ATPs for each glucose molecule. This step is
the conversion of alpha-ketoglutaric acid to succinic acid.
 at two steps in glycolysis yielding 2 ATPs for each glucose molecule.

Mitochondrial DNA (mtDNA)

The human mitochondrion contains 5–10 identical,
circular molecules of DNA. Each consists of 16,569
base pairs carrying the information for 37 genes which
encode:

 2 different molecules of ribosomal RNA

(rRNA)
 22 different molecules of transfer RNA
(tRNA) (at least one for each amino acid)
  13 polypeptides

The rRNA and tRNA molecules are used in the machinery that synthesizes the 13 polypeptides.

The 13 polypeptides participate in building several protein complexes embedded in the inner
mitochondrial membrane.

 7 subunits that make up the mitochondrial NADH dehydrogenase

 3 subunits of cytochrome c oxidase
 2 subunits of ATP synthase
 cytochrome b

Each of these protein complexes also requires subunits that are encoded by nuclear genes,
synthesized in the cytosol, and imported from the cytosol into the mitochondrion. Nuclear genes
also encode ~900 other proteins that must be imported into the mitochondrion. [More]

Mutations in mtDNA cause human diseases.

A number of human diseases are caused by mutations in genes in our mitochondria:

 cytochrome b
 12S rRNA
 ATP synthase
 subunits of NADH dehydrogenase
 several tRNA genes

Although many different organs may be affected, disorders of the muscles and brain are the most
common. Perhaps this reflects the great demand for energy of both these organs. (Although
representing only ~2% of our body weight, the brain consumes ~20% of the energy produced
when we are at rest.)

Some of these disorders are inherited in the germline. In every case, the mutant gene is received
from the mother because none of the mitochondria in sperm survives in the fertilized egg. Other
disorders are somatic; that is, the mutation occurs in the somatic tissues of the individual.

Example: exercise intolerance

A number of humans who suffer from easily-fatigued muscles turn out to have a mutations in
their cytochrome b gene. Curiously, only the mitochondria in their muscles have the mutation;
the mtDNA of their other tissues is normal. Presumably, very early in their embryonic
development, a mutation occurred in a cytochrome b gene in the mitochondrion of a cell destined
to produce their muscles.

The severity of mitochondrial diseases varies greatly. The reason for this is probably the
extensive mixing of mutant DNA and normal DNA in the mitochondria as they fuse with one
another. A mixture of both is called heteroplasmy. The higher the ratio of mutant to normal, the
greater the severity of the disease. In fact by chance alone, cells can on occasion end up with all
their mitochondria carrying all-mutant genomes — a condition called homoplasmy (a
phenomenon resembling genetic drift).

Why do mitochondria have their own genome?

Many of the features of the mitochondrial genetic system resemble those found in bacteria. This
has strengthened the theory that mitochondria are the evolutionary descendants of a bacterium
that established an endosymbiotic relationship with the ancestors of eukaryotic cells early in the
history of life on earth. However, many of the genes needed for mitochondrial function have
since moved to the nuclear genome.

The recent sequencing of the complete genome of Rickettsia prowazekii has revealed a number
of genes closely related to those found in mitochondria. Perhaps rickettsias are the closest living
descendants of the endosymbionts that became the mitochondria of eukaryotes.

Further discussion of the evolutionary implications of mtDNA.

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12 December 2009