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PROBLEM:
Huntington's disease (HD) is a genetic, progressive, neurodegenerative disease caused by the expansion of a polyglutamine trait in the Huntingtin protein. The main neurological signs and symptoms are caused by the loss of the medium spiny neurons of the striatum. The exact pathogenesis of the disease is unknown but mitochondria, which are positioned at the crossroad of energy production and control of cell death, have been heavily implicated.
RESULTS:
Here, we demonstrate that a feed‐forward loop of mitochondrial fragmentation and alterations of their ultrastructure play an important role in determining the susceptibility of HD cellular models to apoptosis. This loop is sustained by the activation of dynamin related protein 1, a large GTP hydrolysing enzyme that is a key mediator of mitochondrial fission. Its genetic blockage restores mitochondrial morphology and the response to apoptosis in the HD models tested.
IMPACT:
Our findings extend the potential therapeutic targets to interfere with the natural history of HD to mitochondrial morphology.
INTRODUCTION
During apoptosis, mitochondria are key organelles to sense and amplify damage, releasing cytochrome c and other cofactors for the effector caspases that dismantle the cell (Danial & Korsmeyer, 2004). This release, tightly controlled by proteins of the Bcl‐2 family, is accompanied by fragmentation of the mitochondrial network (Frank et al, 2001) and remodelling of the mitochondrial cristae (Scorrano et al, 2002). Both processes are required for the progression of apoptosis and cristae remodelling is downstream of fragmentation (Germain et al, 2005). During cell life and death, mitochondrial shape is regulated by a growing family of pro‐fission (the cytoplasmic dynamin related protein 1, Drp1; and its mitochondrial receptor fission‐1, Fis1) and pro‐fusion (the large GTPases Optic Atrophy 1, Opa1, in the inner membrane and Mitofusin, Mfn, 1 and 2 in the outer mitochondrial membrane) mitochondria‐shaping proteins (Liesa et al, 2009).
Neurons are highly dependent on mitochondria, since they are characterized by high energy demands and are unable to switch to glycolysis when mitochondrial oxidative phosphorylation is impaired. A large number of neurodegenerative diseases are indeed caused by an impairment of mitochondrial function (Bossy‐Wetzel et al, 2003). More recently, mutations in the genes coding for mitochondria‐shaping proteins have been associated with some genetic neurodegenerative diseases, implicating mitochondrial shape...