270
chapter 14
Electron Transport and Oxidative Phosphorylation
mtDNA mutation over the age of 60 may suffer severe mul-
tisystem neurological disease. In general, older individu-
als have a lower threshold for oxidative phosphorylation
dysfunction without clinical consequences.
Two tRNALeu(UUR) point mutations account for the ma-
jority of MELAS patients. An A-to-G transition at 3243
has been found in approximately 80% of MELAS pa-
tients. The 3243 mutation alters a highly conserved nu-
cleotide within the dihydrouridine loop of the leucine
tRNA. Unlike the MERRF variants, the 3243 mutation can
result in a number of different clinical syndromes in addi-
tion to MELAS. These include diabetes mellitus and deaf-
ness, cardiomyopathy and ocular myopathy. Other mu-
tations to tRNALeu result in mitochondrial myopathy as
well as late-onset hypertrophic cardiomyopathy and my-
opathy. Overall, the mtDNA tRNA mutations affect both
CNS and skeletal/cardiac muscle tissue while missense
mutations primarily affect nervous tissue. Only one mito-
chondrial rRNA point mutation has been associated with
disease. The homoplasmic A-to-G transition at position
1555 of the 12S rRNA gene is associated with maternally
inherited deafness and aminoglycoside-induced deafness.
mtDNA Deletions and Duplications
Large mtDNA deletions account for most cases of
ocu-
lar myopathy
and
Pearson ’s marrow/pancreas syndrome.
Ocular myopathy patients can exhibit a variety of clinical
symptoms, from mild chronic progressive external oph-
thalmoplegia (CPEO) to
Kearns-Sayre Syndrome (KSS).
These diseases are characterized by an early onset of
ophthalmoplegia, atypical retinitis pigmentosa, mitochon-
drial myopathy, and usually cerebellar syndrome and car-
diac conduction abnormalities. More than 120 different
mtDNA deletions have been identified from patients’ tis-
sues. Partial duplications of mtDNA have been detected in
ocular myopathy
and
Pearson ’s syndrome',
however, du-
plications are much rarer than spontaneous deletions in pa-
tients with these conditions. Exactly how partial mtDNA
duplications arise is unknown.
Patients with mitochondrial disorders may present at
any age and show variation in both the severity and kind
of symptoms associated with a single genetic abnormality.
For example, the tRNALeu(UUR; mutation is predominantly
associated with the neurological syndrome MELAS but
may also be manifested as CPEO, myopathy, diabetes,
and deafness.
Mitochondriopathies associated with severe limitation
of aerobic metabolism in such organs as liver, kidney,
heart, and brain are probably incompatible with survival.
Milder mitochondrial disorders may become clinically ob-
servable when cellular energy demand is not satisfied (e.g.,
exercise intolerance). Despite major advances in our un-
derstanding of mitochondrial disease, treatment options
are limited. Pharmacological therapies have been reported
to be of some benefit in isolated cases. In two sisters
with NADH-CoQ reductase deficiency who exhibited ex-
ercise intolerance, the
3 1
P-NMR study of forearm muscles
showed an abnormally rapid decrease in phosphocreatine
levels during light exercise and a very slow recovery to
normal phosphocreatine and pH levels in the postexercise
period.
3 1
P-NMR spectroscopy has also been used to eval-
uate the bioenergetic capacity of skeletal muscle in a pa-
tient with a history of progressive muscle weakness and
lactic acidosis. The defect resides between Q and cy-
tochrome c (i.e., in complex III); in particular, it is related
to reduced levels of cytochrome b and to a deficiency of
at least four additional polypeptides of complex III. Ad-
ministration of appropriate redox mediators, menadione
(vitamin K
3
), and ascorbate (vitamin C) bypasses the de-
ficient complex III and allows for the transport of electrons
from Q to cytochrome c:
NADH -
•CoQ ■
Cyt b — ► Cyt c ,— ► Cyt c, — ► Cyî c — ► Cyt a + a3
Deficient
Step
Although the bypass pathway for electron transport the-
oretically decreases ATP production by 33% of normal
mitochondria, in this individual it improves phosphoryla-
tion and functional activity.
14.7 Other Reducing-Equivalent Transport
and Oxygen-Consuming Systems
In most cells, more than 90% of the oxygen utilized
is consumed in the respiratory chain that is coupled to
the production of ATP. However, electron transport and
oxygen utilization occur in a variety of other reactions, in-
cluding those catalyzed by oxidases or oxygenases. Xan-
thine oxidase, an enzyme involved in purine catabolism
(Chapter 27), catalyzes the oxidation of hypoxanthine to
xanthine, and of xanthine to uric acid. In these reactions,
reducing equivalents are transferred via FAD, and Fe3+
and Mo6+, while the oxygen is converted to superoxide
anion (O
2
):
h
2
o ,o
2
h +, o
2
H y p o x a n th in e ■
H
2
0 , 0
2
h +, o 2 -
X a n th in e ■
U ric a cid
