Abstract
Polyglutamine expansions in huntingtin (Htt) are known to cause the profound neurodegenerative disorder, Huntington's disease (HD). Mitochondrial dysfunction has long been implicated in the pathophysiology of HD, but the underlying mechanism remains obscure. An article by Costa et al in this months edition describes a smooth mechanistic cascade from the well-accepted upstream event that mutant Htt is associated with Ca2+ handling abnormalities, through to apoptotic neuronal death. The proposed cascade implicates calcineurin, activated by abnormal Ca2+ levels, in the dephosphorylation of dynamin-1-like protein (Drp1), increasing its association with mitochondria and promoting fission, cristae disruption, cytochrome c release and apoptosis (Fig 1). Together with the recent reports of increased mitochondrial fission in striatal neurons from HD patients, the article by Costa et al provides a compelling case for the role of abnormal mitochondrial networking in HD pathogenesis.
Highlights
Scientists of a certain age will remember being taught that mitochondria were discrete, static organelles present at large numbers in virtually all eukaryote cells
The resultant dynamic mitochondrial network has become commonplace to cell biologists, but what is its physiological function? the exact role of mitochondrial fission and fusion has yet to be resolved, it is clear that mitochondrial dynamics are essential for cell viability
Mitochondrial dysfunction has long been proposed to play a crucial role in Huntington’s disease (HD) pathogenesis, as striatal degeneration can be recapitulated with systemically administered mitochondrial inhibitors and decreased activity of mitochondrial respiratory complexes has been found in postmortem striatum from HD patients
Summary
Mitochondrial dysfunction has long been proposed to play a crucial role in Huntington’s disease (HD) pathogenesis, as striatal degeneration can be recapitulated with systemically administered mitochondrial inhibitors and decreased activity of mitochondrial respiratory complexes has been found in postmortem striatum from HD patients. Mounting evidence suggests that mutant huntingtin (Htt) or its polyQcontaining N-terminal fragments can affect mitochondrial function, either in soluble or aggregate form. Has been proposed, ranging from direct Htt–mitochondria association to indirect transcriptional dysregulation affecting mitochondrial composition (Oliveira, 2010). While the focus has traditionally been on altered mitochondrial bioenergetics compromising adenosine triphosphate (ATP) generation and Ca2þ handling, the spotlight has recently turned towards changes in mitochondrial dynamics. Reduced mitochondrial biogenesis, impaired mitochondrial movement along neuronal processes and fusion– fission imbalance have all been proposed to play a role in HD pathogenesis
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