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News and Views
Cell biology: A clean energy programme
Nature 444, 151-152 (9 November 2006)
Mitochondria supply cells with energy, but in the process
produce
potentially damaging oxidants. It seems that a protein
required to produce
new mitochondria also protects against the resulting
oxidative damage.
Toren Finkel

Mitochondria supply cells with energy, but in the process
produce
potentially damaging oxidants. It seems that a protein
required to produce
new mitochondria also protects against the resulting
oxidative damage.

Climate scientists have taught us that the planet is getting
warmer because
of the intimate relationship between the production and
consumption of
energy and the consequent generation of toxic by-products.
Cell biologists
have long known that a similar struggle between product and
by-product
occurs continuously inside every cell. Ground zero for this
intracellular
battle is located in the mitochondria, tiny and
evolutionarily ancient
energy-producing organelles. Writing in Cell, Spiegelman and
colleagues1
suggest that these structures might be able to teach modern
cell
biologists - and those concerned about global warming - a
few lessons on
handling the delicate balance between producing what we
need, while not
ruining what we have.

Much like any factory producing widgets, mitochondria
consume carbon-based
fuels. Their product is ATP, the energy currency of the
cell. Nonetheless,
just like factory smokestacks, mitochondria also release
potentially harmful
by-products into their environment. For mitochondria, these
toxins come in
the form of reactive oxygen species (ROS) that include
superoxide and
hydrogen peroxide. In turn, these oxidants can interact with
other radical
species or with transition metals to produce by-products
that are even more
damaging. To combat ROS production, the cell has evolved a
number of
sophisticated antioxidant defences, including enzymes such
as superoxide
dismutase to scavenge superoxide, as well as catalase and
glutathione
peroxidase to degrade hydrogen peroxide.

Spiegelman and colleagues1 show that treating cells with
extra (exogenous)
hydrogen peroxide stimulates the production of several
antioxidant enzymes,
including catalase, glutathione peroxidase and various forms
of superoxide
dismutase. This effect occurs through increased
transcription, the initial
step of gene expression, and it seems to require a nuclear
protein called
PGC-1. Spiegelman and colleagues first described PGC-1
several years ago,
and it is now clear that this protein belongs to a family of
coactivators
that includes PGC-1 and PRC (ref. 2). Coactivators are
proteins that
regulate gene transcription, usually in a tissue-specific
fashion.
Curiously, these factors don't actually bind to regulatory
sequences in DNA.
Instead, they often act as molecular scaffolds to
turbo-charge gene
expression. They do this by recruiting various DNA-modifying
enzymes while
simultaneously interacting with classical transcription
factors that bind to
DNA. Interest in PGC-1 escalated when it was realized that
this particular
coactivator has a major role in creating new mitochondria
when they are
needed by the cell, in a process known as mitochondrial
biogenesis3.

In their latest experiments1, Spiegelman and colleagues show
that
simultaneously reducing the amounts of PGC-1 and PGC-1
essentially
eliminates the cell's ability to increase its antioxidant
defences in
response to exogenous ROS. Their experiments suggest that
although PGC-1 is
involved in this response, most of the transcriptional
drudgery is done by
PGC-1. Indeed, they show that cells from PGC-1-deficient
animals have
increased basal levels of ROS and a reduced ability to
withstand damage from
these toxins. Similarly, overproduction of PGC-1 in neuronal
progenitor
cells allowed those cells to become more resistant to
oxidative stress.

These in vitro results were mirrored by in vivo
observations. For instance,
treatment of mice lacking PGC-1 with two known inducers of
neurological
oxidative stress, MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and
kainic acid, caused significantly more neuronal damage than
did similar
treatment of control mice. In the 1980s, MPTP caused severe
Parkinson's
disease in a group of drug abusers who accidentally ingested
this toxin. It
is now known that in these unfortunate individuals MPTP was
acting as a
highly specific inhibitor of mitochondrial electron
transport. Similarly,
kainic acid treatment is widely used as a model of neuronal
damage and
epilepsy.

Together with previous work, these results suggest that
PGC-1 can increase
the number of mitochondria while also protecting the cell
from subsequent
mitochondrion-induced damage. In essence, it is as though
PGC-1 is building
the factory and starting the environmental clean-up at the
same time. The
observation that this protein can regulate the oxidative
balance in cells
might also provide insight into some unexplained traits
observed in mice
lacking PGC-1. Such animals exhibit striking behavioural
changes, including
increased anxiety and hyperactivity4, 5. Although these
behavioural changes
may relate to structural changes seen in the brains of
PGC-1-deficient mice,
an independent group working on the genetic basis of anxiety
has implicated
ROS metabolism in this complex trait6. Are the behavioural
changes in the
PGC-1-deficient mice also due to an absence of antioxidant
defences? If so,
does this imply that what cell biologists call oxidative
stress and what
social scientists call psychological stress might ultimately
share a common
mechanism? Further study is necessary, but people who fear
public speaking
may take some comfort in the notion that the problem might
not be in their
head but rather, more specifically, in their mitochondria.

The work of Spiegelman and colleagues1 brings up another
interesting aspect
of mitochondrial biology. It is well known that these
organelles, whether
they come from simple organisms or complex mammals, all leak
measurable
amounts of ROS. Experimental systems that simply increase
the production of
antioxidant proteins seem to be quite effective at reducing
this leakage. If
ROS synthesis is so bad, and a molecular solution so apparently
straightforward, why has this 'design flaw' not been
eradicated during the
billions of years of evolution? There are many possible
answers, but one is
that the notion that ROS from the mitochondria are solely
harmful could be
incorrect. Indeed, substantial evidence exists that ROS
generated in the
cytoplasm could have vital signalling functions7, and this
might also be
true for oxidants derived from mitochondria8, 9. The new
study1 strengthens
this possibility and suggests that a homeostatic loop exists
between
mitochondria and ROS and that this loop is, at least in
part, orchestrated
by PGC-1 (Fig. 1).

Figure 1: PGC-1 in mitochondrial biogenesis and antioxidant
defence1, 2, 3.
Many external stimuli that signal an increase in the need
for energy can
activate PGC-1. By acting on members of the nuclear-receptor
superfamily -
including NRF-1, NRF-2 and ERR- - PGC-1 can induce
mitochondrial biogenesis.
The resulting production of reactive oxygen species (ROS;
oxidative stress)
may feed back through the CREB gene-regulatory factor,
leading to further
increases in PGC-1. This oxidant-induced increase in PGC-1
is then necessary
to stimulate expression of a host of antioxidant proteins,
including forms
of superoxide dismutase (SOD), glutathione peroxidase (GPx)
and catalase.

Previous reports have suggested that certain life-extending
strategies, such
as calorie restriction, might work through the PGC-1-induced
mitochondrial
biogenesis programme10. Spiegelman and colleagues' study
suggests that PGC-1
could also alter our susceptibility to neurodegenerative
conditions that are
linked to mitochondrial dysfunction and oxidative stress,
such as
Parkinson's disease. Therefore, fine-tuning the activity of
this resourceful
coactivator might have a wide range of clinical benefits,
including
potentially allowing us to live longer and think more
clearly. Not a bad set
of objectives, especially if we are ultimately going to need
to tackle
really tricky problems like global warming.

1. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J,
Jager S, Handschin
C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM.
Suppression of reactive oxygen species and neurodegeneration
by the PGC-1
transcriptional coactivators.
Cell. 2006 Oct 20;127(2):397-408.
PMID: 17055439

PPARgamma coactivator 1alpha (PGC-1alpha) is a potent
stimulator of
mitochondrial biogenesis and respiration. Since the
mitochondrial electron
transport chain is the main producer of reactive oxygen
species (ROS) in
most cells, we examined the effect of PGC-1alpha on the
metabolism of ROS.
PGC-1alpha is coinduced with several key ROS-detoxifying
enzymes upon
treatment of cells with an oxidative stressor; studies with
RNAi or null
cells indicate that PGC-1alpha is required for the induction
of many
ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1alpha
null mice are
much more sensitive to the neurodegenerative effects of MPTP
and kainic
acid, oxidative stressors affecting the substantia nigra and
hippocampus,
respectively. Increasing PGC-1alpha levels dramatically
protects neural
cells in culture from oxidative-stressor-mediated death.
These studies
reveal that PGC-1alpha is a broad and powerful regulator of
ROS metabolism,
providing a potential target for the therapeutic
manipulation of these
important endogenous toxins.