Mitochondria

Over a billion years ago, aerobic bacteria were engulfed by eukaryotic cells and evolved into
mitochondria, providing the eukaryotic cells with the ability to form the energy-rich compound
ATP by oxidative phosphorylation. Mitochondria perform other functions, including a role in
the regulation of apoptosis (programmed cell death), but oxidative phosphorylation is the most
crucial. Each eukaryotic cell can have hundreds to thousands of mitochondria. In mammals, they
are generally depicted as sausage-shaped organelles (Figure 21), but their shape can be quite
dynamic. Each has an outer membrane, an intermembrane space, an inner membrane, which is
folded to form shelves (cristae), and a central matrix space. The enzyme complexes responsible
for oxidative phosphorylation are lined up on the cristae (Figure 24).
Figure 24

Components involved in oxidative phosphorylation in mitochondria and their origins. As

enzyme complexes I through IV convert 2-carbon metabolic fragments to CO2 and H2O,
protons (H+) are pumped into the intermembrane space. The proteins diffuse back to the matrix
space via complex V, ATP synthase (AS), in which ADP is converted to ATP. The enzyme
complexes are made up of subunits coded by mitochondrial DNA (mDNA) and nuclear DNA
(nDNA), and the figures document the contribution of each DNA to the complexes.
Consistent with their origin from aerobic bacteria, the mitochondria have their own genome.
There is much less DNA in the mitochondrial genome than in the nuclear genome, and 99% of
the proteins in the mitochondria are the products of nuclear genes, but mitochondrial DNA is
responsible for certain key components of the pathway for oxidative phosphorylation.
Specifically, human mitochondrial DNA is a double-stranded circular molecule containing
approximately 16,500 base pairs (compared with over a billion in nuclear DNA). It codes for 13
protein subunits that are associated with proteins encoded by nuclear genes to form four enzyme
complexes plus two ribosomal and 22 transfer RNAs that are needed for protein production by
the intramitochondrial ribosomes.
The enzyme complexes responsible for oxidative phosphorylation illustrate the interactions
between the products of the mitochondrial genome and the nuclear genome. For example,
complex I, reduced nicotinamide adenine dinucleotide dehydrogenase (NADH), is made up of 7
protein subunits coded by mitochondrial DNA and 39 subunits coded by nuclear DNA. The
origin of the subunits in the other complexes is shown in Figure 24. Complex II, succinate
dehydrogenase-ubiquinone oxidoreductase; complex III, ubiquinone-cytochrome c
oxidoreductase; and complex IV, cytochrome c oxidase, act with complex I, coenzyme Q, and
cytochrome c to convert metabolites to CO2 and water. Complexes I, III, and IV pump protons
(H+) into the intermembrane space during this electron transfer. The protons then flow down
their electrochemical gradient through complex V, ATP synthase, which harnesses this energy to
generate ATP.

As zygote mitochondria are derived from the ovum, their inheritance is maternal. This maternal
inheritance has been used as a tool to track evolutionary descent. Mitochondria have an
ineffective DNA repair system, and the mutation rate for mitochondrial DNA is over 10 times
the rate for nuclear DNA. A large number of relatively rare diseases have now been traced to
mutations in mitochondrial DNA. These include for the most part disorders of tissues with high
metabolic rates in which energy production is defective as a result of abnormalities in the
production of ATP.

Alta carte

The mitochondria (!A, B; p. 17 B) are the

site of oxidation of carbohydrates and lipids to
CO2 and H2O and associated O2 expenditure.
The Krebs cycle (citric acid cycle), respiratory
chain and related ATP synthesis also occur in
mitochondria. Cells intensely active in metabolic
and transport activities are rich in mitochondria
e.g., hepatocytes, intestinal cells,
and renal epithelial cells. Mitochondria are enclosed
in a double membrane consisting of a
smooth outer membrane and an inner membrane.
The latter is deeply infolded, forming a
series of projections (cristae); it also has important
transport functions (!p. 17 B). Mitochondria
probably evolved as a result of symbiosis
between aerobic bacteria and anaerobic
cells (symbiosis hypothesis). The mitochondrial
DNA (mtDNA) of bacterial origin and the
double membrane of mitochondria are relicts
of their ancient history. Mitochondria also
contain ribosomes which synthesize all proteins
encoded by mtDNA.

Alta carte 2

Mitochondria
Mitochondria (mito-kondre-ah) are threadlike (mitos = thread) or sausage-shaped membranous
organelles (Figure 3.17). In living cells they squirm, elongate, and change shape almost continuously.
They are the power plants of a cell, providing most of its ATP supply. The density of mitochondria in a
particular cell reflects that cells energy requirements, and mitochondria are generally clustered where
the action is. Busy cells like kidney and liver cells have hundreds of mitochondria, whereas relatively
inactive cells (such as unchallenged lymphocytes) have just a few. Mitochondria are enclosed by two
membranes, each with the general structure of the plasma membrane. The outer membrane is smooth
and featureless, but the inner membrane folds inward, forming shelflike cristae (krste; crests) that
protrude into the matrix, the gel-like substance within the mitochondrion. Intermediate products of
food fuels (glucose and others) are broken down to water and carbon dioxide by teams of enzymes,
some dissolved in the mitochondrial matrix and others forming part of the crista membrane.
As the metabolites are broken down and oxidized, some of the energy released is captured and used
to attach phosphate groups to ADP molecules to form ATP. This multistep mitochondrial process
(described in Chapter 24) is generally referred to as aerobic cellular respiration (a-er-obik) because it
requires oxygen.
Mitochondria are complex organelles: They contain their own DNA and RNA and are able to reproduce
themselves. Mitochondrial genes (some 37 of them) direct the synthesis of some 5% of the proteins
required for mitochondrial function, and the DNA of the cells nucleus encodes the remaining proteins
needed to carry out cellular respiration. When cellular requirements for ATP increase, the mitochondria
synthesize more cristae or simply pinch in half (a process called fission) to increase their number, then
grow to their former size.
Intriguingly, mitochondria are similar to a specific group of bacteria (the purple bacteria phylum), and
mitochondrial DNA is similar to that found in bacterial cells. It is now widely believed that mitochondria
arose from bacteria that invaded the ancient ancestors of plant and animal cells.

FIGURE 3.17 Mitochondrion. (a) Diagrammatic view of a

longitudinally sectioned mitochondrion. (b) Electron microg

Mitochondria38 (MY-toe-CON-dree-uh) (fig. 3.29) are

organelles specialized for synthesizing ATP. They have a
variety of shapes: spheroid, rod-shaped, kidney bean
shaped, or threadlike. Like the nucleus, a mitochondrion
is surrounded by a double unit membrane. The inner
membrane usually has folds called cristae39 (CRIS-tee),
which project like shelves across the organelle. The space

FIGURE 3.29 A Mitochondrion.

between the cristae, called the matrix, contains ribosomes;
enzymes used in ATP synthesis; and a small, circular
DNA molecule called mitochondrial DNA (mtDNA).
Mitochondria are the powerhouses of the cell. Energy is
not made here, but it is extracted from organic compounds
and transferred to ATP, primarily by enzymes
located on the cristae. The role of mitochondria in ATP

synthesis is explained in detail in chapter 26, and some

evolutionary and clinical aspects of mitochondria are discussed
at the end of this chapter

MitochondriaEvolution and Clinical

Significance
It is virtually certain that mitochondria evolved from bacteria
that invaded another primitive cell, survived in its cytoplasm,
and became permanent residents. Certain modern bacteria
called ricketsii live in the cytoplasm of other cells, showing that
this mode of life is feasible. The two unit membranes around the
mitochondrion suggest that the original bacterium provided
the inner membrane, and the host cells phagosome provided
the outer membrane when the bacterium was phagocytized.
Several comparisons show the apparent relationship of
mitochondria to bacteria. Their ribosomes are more like bacterial
ribosomes than those of eukaryotic (nucleated) cells.
Mitochondrial DNA (mtDNA) is a small, circular molecule that
resembles the circular DNA of bacteria, not the linear DNA of
the cell nucleus. It replicates independently of nuclear DNA.
Mitochondrial DNA codes for some of the enzymes employed
in ATP synthesis. It consists of 16,569 base pairs (explained in
chapter 4), comprising 37 genes, compared with over 3 billion
base pairs and about 25,000 to 35,000 genes in nuclear DNA.
When a sperm fertilizes an egg, any mitochondria introduced
by the sperm are usually destroyed and only those provided by
the egg are passed on to the developing embryo. Therefore,
mitochondrial DNA is inherited almost exclusively through the
mother. While nuclear DNA is reshuffled in every generation by
sexual reproduction, mtDNA remains unchanged except by random
mutation. Biologists and anthropologists have used mtDNA
as a molecular clock to trace evolutionary lineages in humans
and other species. Mitochondrial DNA has also been used as
evidence in criminal law and to identify the remains of soldiers
killed in combat. It was used in 2001 to identify the remains of
the famed bandit Jesse James, who was killed in 1882.
Anthropologists have gained evidence that of all the women who
lived in Africa 200,000 years ago, only one has any descendants
still living today. This mitochondrial Eve is ancestor to us all.
Mitochondrial DNA is very exposed to damage from free
radicals normally generated in mitochondria by aerobic
respiration. Yet unlike nuclear DNA, mtDNA has no effective
mechanism for repairing damage. Therefore, it mutates about
10 times as rapidly as nuclear DNA. Some of these mutations
are responsible for various rare hereditary diseases and
death in early childhood. Tissues and organs with the highest
energy demands are the most vulnerable to mitochondrial
dysfunctionsnervous tissue, the heart, the kidneys, and
skeletal muscles, for example.
Mitochondrial myopathy is a degenerative muscle disease in
which the muscle displays ragged red fibers, cells with abnormal
mitochondria that stain red with a particular histological

The Cytoskeleton
The cytoskeleton is a collection of protein filaments and
cylinders that determine the shape of a cell, lend it structural
support, organize its contents, direct the movement of
substances through the cell, and contribute to movements
of the cell as a whole. It can form a very dense supportive
scaffold in the cytoplasm (fig. 3.31). It is connected to
transmembrane proteins of the plasma membrane, and
they in turn are connected to protein fibers external to the
cell, so there is a strong structural continuity from extracellular
material to the cytoplasm. Cytoskeletal elements may

even connect to chromosomes in the nucleus, enabling

physical tension on a cell to move nuclear contents and
mechanically stimulate genetic function.
The cytoskeleton is composed of microfilaments, intermediate
filaments, and microtubules. Microfilaments are
about 6 nm thick and are made of the protein actin. They
form a network on the cytoplasmic side of the plasma
membrane called the terminal web (membrane skeleton).
The phospholipids of the plasma membrane spread out
over the membrane skeleton like butter on a slice of bread.
Like butter acting as a moisture barrier in a sandwich, the
phospholipids of the plasma membrane act as a permeability
barrier at the cell surface, whereas the terminal web,
like the bread, provides physical support. It is thought that
the phospholipids would break up into little droplets without
this cytoskeletal bed.
The roles of actin in supporting microvilli and producing
cell movements were discussed earlier. Through
its role in cell motility, actin plays a crucial role in embryonic
development, muscle contraction, immune function,
wound healing, cancer metastasis, and other processes
that involve cell migration.
Intermediate filaments (810 nm in diameter) are
thicker and stiffer than microfilaments. They resist stresses
placed on a cell and participate in junctions that attach
some cells to their neighbors. In epidermal cells, they are
made of the tough protein keratin and occupy most of the
cytoplasm. They are responsible for the strength of hair
and fingernails. Intermediate filaments also line the
inside of the nuclear envelope and form the cagelike
nuclear lamina that encloses the DNA.
A microtubule (25 nm in diameter) is a cylinder made
of 13 parallel strands called protofilaments. Each protofilament
is a long chain of globular proteins called tubulin
(fig. 3.32). Microtubules radiate from the centrosome and stain. Mitochondrial encephalomyopathy, lactic acidosis and
strokelike episodes (MELAS) is a mitochondrial syndrome involving
seizures, paralysis, dementia, muscle deterioration, and a toxic
accumulation of lactic acid in the blood. Leber hereditary optic
neuropathy (LHON) is a form of blindness that usually appears in
young adulthood as a result of damage to the optic nerve.
KearnsSayre syndrome (KSS) involves paralysis of the eye muscles,
degeneration of the retina, heart disease, hearing loss, diabetes,
and kidney failure. Damage to mtDNA has also been
implicated as a possible factor in Alzheimer disease, Huntington
disease, and other degenerative diseases of old age. the mitotic spindle that guides chromosome movement

during cell division. Microtubules are not permanent

structures. They come and go moment by moment as tubulin
molecules assemble into a tubule and then suddenly
break apart again to be used somewhere else in the cell.
The double and triple sets of microtubules in cilia, flagella,
basal bodies, and centrioles, however, are more stable.

raph of a mitochondrion (28,400).