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10 | advancing Knowledge
Energy gap
Cold cures
Mitochondrial DNA mutations are
surprisingly common.
Not all pain is the same.
1 2 3
Mitochondria generate the bulk of the
cell’s energy. Derived from once-freeliving
bacteria, they retain the remnants
of an ancestral genome, now down to
its last 37 genes. Mutations in these
genes cause a variety of conditions,
typically affecting tissues with high
energy needs, yet their full impact has
been obscure. Now, Patrick Chinnery,
Doug Turnbull and colleagues at
Newcastle University have found that
they affect significantly more people
than previously thought.
The Newcastle group used two
approaches to assess the incidence of
mitochondrial DNA mutations. One was
to assess how many new mutations
appeared in a series of more than 3000
live births. One in 200 was found to carry
a mutation not seen in their mother.
In a complementary strand of work, the
researchers calculated the prevalence of
mutations in the working-age population
around Newcastle, by analysing all
suspected cases of mitochondrial
disease seen at a neurology clinic
between 1990 and 2004.
By tracing family members, they found
that 9.2 in 100 000 people had clinically
apparent mitochondrial DNA disease,
making it one of the most common
inherited neuromuscular disorders.
In addition, a further 16.5 in 100 000
children and adults were at risk of
mitochondrial DNA disease.
The inheritance of mitochondrial DNA
disorders is complex – the severity of
symptoms varies widely in the offspring
of affected mothers. Offspring get all their
mitochondria from their mother, but if
she has a mix of normal and mutant
mitochondria, what decides whether they
receive normal or affected mitochondria
or a mix of both?
The answer, it appears, is pure luck. When
the Newcastle team looked at the
precursors of egg cells created early in
development, they discovered that the
cells inherited a random selection of
mutant and normal mitochondria. What
an offspring ends up with simply depends
on the fraction of mutant mitochondria in
the egg that gets fertilised.
Discovery of this ‘mitochondrial genetic
bottleneck’ may provide an opportunity
to screen out eggs with many mutant
mitochondria, reducing the risk that a
mother has a severely affected child.
Schaefer AM et al. Prevalence of mitochondrial
DNA disease in adults. Ann Neurol 2008;63(1):35–9.
Elliott HR et al. Pathogenic mitochondrial DNA
mutations are common in the general population.
Am J Hum Genet 2008;83(2):254–60.
Cree LM et al. A reduction of mitochondrial DNA
molecules during embryogenesis explains the rapid
segregation of genotypes. Nat Genet 2008;40(2):
249–54.
Many noxious insults trigger pain,
such as heat, cold and tissue damage.
All these insults are detected by
pain-sensing neurons, nociceptors,
which rapidly send messages to the
spinal cord and then on to the brain.
But there are subtle differences in how
they are detected, and John Wood of
University College London and
colleagues are unpicking the cellular
mechanisms that distinguish different
types of pain.
Although cold tends to inhibit our sensory
and motor systems, pain perception is
not affected – it serves a valuable defence
function. To explore the mechanisms
underlying this effect, Professor Wood’s
team examined the function of key
nociceptor sodium channels, the
activation of which triggers a nerve
impulse and ultimately leads to the
sensation of pain.
While the activity of most types of channel
dropped when skin was cooled, that of
one specific channel – known as Na v 1.8
– was unaffected. Moreover, chilling
actually lowered the threshold at which
Na v 1.8 channels opened. Thus Na v 1.8
appears to be the crucial element of cold
pain sensing by nociceptors.
But are there specific nociceptors for pain
or does each sensory neuron detect a
range of stimuli? To address this question,
Professor Wood used a toxin to eliminate
Images
1 Mitochondria, the cell’s source of energy.
2 Cardiac muscle stained for mitochondria.
3, 4 Toxin-induced elimination of Na v 1.8 neurons (green).
5, 6 Chromosomes (blue) are moved in dividing cells by microtubules
(red), which attach to kinetochores (green)