Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli
Article first published online: 10 NOV 2010
Copyright © 2010 EMBO Molecular Medicine
EMBO Molecular Medicine
Volume 2, Issue 12, pages 490–503, December 2010
How to Cite
Costa, V., Giacomello, M., Hudec, R., Lopreiato, R., Ermak, G., Lim, D., Malorni, W., Davies, K. J. A., Carafoli, E. and Scorrano, L. (2010), Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli. EMBO Mol Med, 2: 490–503. doi: 10.1002/emmm.201000102
- Issue published online: 10 DEC 2010
- Article first published online: 10 NOV 2010
- Manuscript Accepted: 1 OCT 2010
- Manuscript Revised: 29 SEP 2010
- Manuscript Received: 29 JAN 2010
- cristae remodelling;
- Huntington's disease;
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.
See accompanying Closeup by Oliveira and Lightowlers DOI 10.1002/emmm.201000104.