Nuclear Control of Respiratory Chain Expression
diseases. Somatic mutations accumulate in somatic
tissues and exacerbate inherited oxidative
phosphosphorylation defects. The high mtDNA
mutation rate may be due to the high concentration of
oxygen radicals at the mitochondrial inner membrane,
the lack of efficient mtDNA repair mechanisms and/or
the absence of histones.
• Cellular oxygen utilization decreases as a function of
age and the ATP generating capacity of the cell is a
function of age. The attenuation of ATP synthesis is
associated with an age-related increase in somatic
mtDNA damage in postmitotic tissue. The “normal”
decline in ATP generating capability may facilitate
disease occurrence when it is associated with an
inherited oxidative phosphorylation mutation.
Mitochondrial biogenesis incorporates two distinct pro-
of mitochondrial membranes in which
the synthesis of both outer and inner compartments is
linked closely to the cell cycle; and
of the organelle for respiratory chain
phosphorylation, requiring coordinated control of
both nuclear and mitochondrial genes. This is
independent of cell growth and division.
The supply of lipids for mitochondrial membrane biosyn-
thesis depends largely on lipids synthesized elsewhere
in the cell, especially the endoplasmic reticulum. How-
ever, one major lipid component of the inner mitochon-
synthesized within the mitochondria.
The formation of functional enzyme complexes within
the inner mitochondrial membrane proceeds through the
sequential assembly of subunits. In assembly of complex
I, nuclear encoded subunits form the inner core of the com-
plex followed by attachment of mtDNA encoded subunits.
Mitochondrial proteins synthesized in the cytosol contain
information that guide them to the mitochondria (intra-
cellular targeting) and that direct their incorporation to a
specific site. This information resides in a signal sequence
since mitochondrial proteins lacking all or a part of their
sequences are not transported into mitochondria. The sig-
nal sequences share the property of having a high content
of basic and hydroxylated amino acids, no acidic amino
acids, and stretches of hydrophobic sequences.
One disorder of mitochondrial transport in humans is
due to a failure to transport the methylmalonyl-CoA-
mutase precursor protein. The mutation responsible for
this disorder affects the signal sequence region. An-
other disorder has been ascribed to the transport of ala-
nine glyoxylate aminotransferase, an enzyme normally
located in peroxisomes of human liver, to mitochondria.
The transport of proteins into mitochondria is aided by
an outer membrane protein, the general insertion pro-
tein (GIP). Proteins that reside in the matrix space, in-
ner membrane, or intermembrane space are routed from
the GIP, across the contact site to the matrix space. This
transport requires an electrical potential across the inner
membrane. After crossing the mitochondrial membrane,
precursor polypeptides are converted to mature proteins
by the action of proteolytic enzymes that remove signal
Expression of mtDNA
In addition to limited initiation sites for transcription and
the presence of overlapping reading frames, mtDNA has
other distinctive features, including a codon assignments
that differ from those of nDNA.
1. UGA is used as a tryptophan codon (instead of a stop
2. During translation in mitochondria, unusual codon
recognition is a “two out of three” base interaction
between codon and anticodon.
3. There are no AG A or AGG (arginine) codons in
mtDNA genes. Also, no tRNAs are made in
mitochondria for these codons.
4. A single tRNAmet specifies both methionine tRNA
and N-formylmethionine tRNA by secondary
modification of the primary transcript.
Thus, mitochondria require only 22 tRNA molecules to
read the genetic code as compared to 31 required for the
14.5 Nuclear Control of Respiratory
Nuclear genes contribute the majority of respiratory
subunits and all of the proteins required for mtDNA
transcription, translation, and replication. It is estimated
that more than 80% of the genes encoding the subunits
of the respiratory chain are located in the cell nucleus.
Despite the predominant role for nuclear gene products
in the biogenesis and function of the mitochondrial
respiratory chain, few nuclear genes have been implicated
in mitochondrial genetic disorders. Certain abnormalities
of mtDNA are transmitted as Mendelian traits, and it is
thought that such characteristics are caused by mutation
in identified nuclear genes.