Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli

• Published in: EMBO molecular medicine Vol. 2; no. 12; pp. 490 - 503
• Main Authors: Costa, Veronica, Giacomello, Marta, Hudec, Roman, Lopreiato, Raffaele, Ermak, Gennady, Lim, Dmitri, Malorni, Walter, Davies, Kelvin J. A., Carafoli, Ernesto, Scorrano, Luca
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2010; WILEY‐VCH Verlag; EMBO Press; WILEY-VCH Verlag
• Subjects: Animals; Apoptosis; Calcineurin; Cell culture; Cell death; Cell Line; Cells, Cultured; Cristae; cristae remodelling; Cytochrome; Cytochrome c; Cytochromes c - metabolism; Dynamin; Dynamins; Experiments; Female; fission; Genes; Genetic analysis; Genomes; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humans; Huntingtin; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - physiopathology; Huntington's disease; Huntingtons disease; Hypersensitivity; Male; Mice; Microscopy, Electron, Transmission; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - genetics; Mitochondria - physiology; Mitochondria - ultrastructure; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Models, Biological; Morphology; Mutation; Neurodegenerative diseases; Neurons - cytology; Neurons - metabolism; Pathogenesis; Phosphorylation; Polyglutamine diseases; Protein Transport; Proteins; Research Article; Software; Trinucleotide repeat diseases; apoptosis; Huntington's disease; cristae remodelling; mitochondria; fission
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201000102

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 https://doi.org/10.1002/emmm.201000104 .