Mitofusin
2: a regulator of energy expenditure that contributes to the development
of obesity
The
identification of new targets for obesity therapeutics represents a key
priority for the pharmaceutical industry. This has been driven by the large
and growing numbers of obese individuals around the world, the high incidence
of serious co-morbidities, and a market predicted to reach $3.7 billion by
2008.
Obesity occurs
when calorific intake exceeds energy expenditure. LeadDiscovery has recently
analyzed two emerging anti-obesity targets, ghrelin which regulates food
intake and the retinoids which also plays a role in both food intake as well
as energy expenditure . The latter has attracted considerable interest with
respect to obesity and since the mitochondria is responsible for cellular
metabolism mitochondrial proteins have represented a focus of attention. For
example the uncoupling proteins which uncouple substrate metabolism from ATP
production has generated considerable interest. In this edition of
TherapeuticAdvances we highlight another mitochondrial target, mitofusin, a
protein which contributes to mitochondrial integrity.
In many cells
and especially myocytes, mitochondria form elongated filaments or a branched
reticulum. Researchers at the University of Barcelona and the associated
spin-off, GeneXartis show that mitofusin 2 (Mfn2), a mitochondrial membrane
protein that participates in mitochondrial fusion in mammalian cells, is
induced during myogenesis and contributes to the maintenance and operation of
the mitochondrial network. Repression of Mfn2 caused morphological and
functional fragmentation of the mitochondrial network into independent
clusters. Concomitantly, repression of Mfn2 reduced glucose oxidation,
mitochondrial membrane potential, cell respiration and mitochondrial proton
leak.
Perhaps of
greatest interest with regards to pathology and therapeutics, the
Mfn2-dependent mechanism of mitochondrial control is disturbed in obesity as a
result of reduced Mfn2 expression. Decreased expression was found in both the
skeletal muscle of Zucker obese rats and in obese humans and a negative linear
relationship between Mfn2 mRNA levels and body mass index has been reported.
These data therefore indicate that Mfn2 expression is crucial to mitochondrial
metabolism through the maintenance of the mitochondrial network architecture,
and reduced Mfn2 expression may explain some of the metabolic alterations
associated with obesity. Further studies exploring the (dys)regulation of Mfn2
expression under control and obese conditions should hopefully lead to the
identification of strategies able to increase mitochondrial metabolism and
hence limit obesity.
Entry date March, 2003
Adapted from
Bach et al, J Biol Chem 2003 Feb 21 - Interested in collaborating with this
group? Contact LeadDiscovery or the authors direct.
Interested
in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk
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