Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli.
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.
Department of Cell Physiology and Medicine, University of Geneva, Geneva, Switzerland.
Veronica
V
Costa
Marta
M
Giacomello
Roman
R
Hudec
Raffaele
R
Lopreiato
Gennady
G
Ermak
Dmitri
D
Lim
Walter
W
Malorni
Kelvin J A
KJ
Davies
Ernesto
E
Carafoli
Luca
L
Scorrano
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D021381:Protein Transport
D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins