Mitochondrial fission and cristae disruption increase the response of cell models of Huntington&#039;s disease to apoptotic stimuli

Costa, Veronica; Giacomello, Marta; Hudec, Roman; Lopreiato, Raffaele; Ermak, Gennady; Lim, Dmitri; Malorni, Walter; Davies, Kelvin J. A.; Carafoli, Ernesto; Scorrano, Luca

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Title		Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli
Authors		Costa, Veronica Giacomello, Marta Hudec, Roman Lopreiato, Raffaele Ermak, Gennady Lim, Dmitri Malorni, Walter Davies, Kelvin J. A. Carafoli, Ernesto Scorrano, Luca show all authors [1 - 10]
Published in		EMBO Molecular Medicine. 2010, vol. 2, no. 12, p. 490-503
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.
Keywords		Animals — Apoptosis — Cell Line — Cells, Cultured — Cytochromes c/metabolism — Female — GTP Phosphohydrolases/genetics/metabolism — Humans — Huntington Disease/genetics/metabolism/physiopathology — Male — Mice — Microscopy, Electron, Transmission — Microtubule-Associated Proteins/genetics/metabolism — Mitochondria/genetics/*physiology/ultrastructure — Mitochondrial Proteins/genetics/metabolism — Models, Biological — Neurons/cytology/metabolism — Protein Transport
Identifiers		DOI: 10.1002/emmm.201000102 PMID: 21069748
Full text		Article - Limited access to UNIGE Other version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044888/pdf/emmm0002-0490.pdf
Structures		Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme
Research group		Les mitochondries dans la vie cellulaire (850)
Citation (ISO format)		COSTA, Veronica et al. Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli. In: EMBO Molecular Medicine, 2010, vol. 2, n° 12, p. 490-503. https://archive-ouverte.unige.ch/unige:20858