| Mitochondria and mitochondrial
disease
Mitochondria are double-membrane organelles that populate
by the hundreds or thousands the cytoplasm of all cells in
the human body. Their main function is to produce energy
through a metabolic process called oxidative phosphorylation
(OXPHOS). More than ninety percent of the energy utilized
by our organism is produced in the mitochondria. When a failure
in energy supply occurs, due to defective mitochondrial OXPHOS,
the life of the cell, and indeed that of our entire organism,
is seriously at risk. Tissues and organs with the highest
energy demand, including the brain, skeletal muscles, and
the heart, are usually the most affected ones.
The OXPHOS process takes place in the internal membrane of
mitochondria, through a sequential series of reactions of
reduction and oxidation, which form the so called “cellular
respiration” and are carried out by the four enzymatic
complexes of the mitochondrial respiratory chain
(Complex I, Complex II, Complex III, Complex IV or cytochrome-c-oxidase).
In this reaction, electrons liberated by the controlled degradation
of nutrients are ultimately combined with molecular oxygen
to produce water. The energy liberated during these reactions
is utilized by Complex V, or ATP-synthetase, to produce the
compound adenosintriphosphate (ATP), the fundamental “fuel”
for cellular metabolism. From a genetic point of view the
respiratory chain has unique features since it is composed
of proteins encoded by two different genetic systems: the
nuclear genome, which is inherited from both
parents, and the mitochondrial genome, which
is inherited exclusively from the mother. As a consequence
of this dual genetic inheritance, OXPHOS defects can be caused
by mutations in either mitochondrial or nuclear genes.
The Mitochondrial Genome
Mitochondria have their own DNA (mtDNA). MtDNA is an extremely
small, circular minichromosome, present in several copies
in each organelle, and containing only thirty-seven genes.
Thirteen genes encode as many protein subunits of the OXPHOS
complexes, whilst twenty-four genes encode RNA molecules (2
ribosomal RNA, rRNA, and 22 transfer RNAs, tRNA) that are
indispensable for the in situ synthesis of the mtDNA-encoded
protein subunits.
During fertilization, mitochondria present in the new individual
(zygote) are derived only from the egg cell. In principle,
a mother carrying a mtDNA mutation will transmit it to all
of her children, but only her daughters will be able to transmit
this mutation on to the subsequent generation. This pattern
of transmission is called maternal inheritance.
In contrast to the double nuclear gene copies, that are called
paternal and maternal alleles, present in human nuclei, there
are hundreds of mtDNA molecules contained in each cell. In
a normal individual, all the mtDNA molecules are identical,
a condition called homoplasmy. Deleterious
mtDNA mutations generally strike only a fraction of the mitochondrial
genomes of an individual, leading to the coexistence in cells
and tissues of two mtDNA populations, one normal and one mutated.
This condition is called heteroplasmy. However,
it is only when the mutated genomes reach a critical threshold
over the normal genomes, that an effective reduction of OXPHOS
activity occurs and thus the clinical manifestations of disease.
|
