Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli.
EMBO Mol Med
; 2(12): 490-503, 2010 Dec.
Article
em En
| MEDLINE
| ID: mdl-21069748
ABSTRACT
Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here, we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells, the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Doença de Huntington
/
Mitocôndrias
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article