Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis.
OPA1 encodes a large GTPase related to dynamins, anchored to the mitochondrial cristae inner membrane, facing the intermembrane space. OPA1 haplo-insufficiency is responsible for the most common form of autosomal dominant optic atrophy (ADOA, MIM165500), a neuropathy resulting from degeneration of the retinal ganglion cells and optic nerve atrophy. Here we show that down-regulation of OPA1 in HeLa cells using specific small interfering RNA (siRNA) leads to fragmentation of the mitochondrial network concomitantly to the dissipation of the mitochondrial membrane potential and to a drastic disorganization of the cristae. These events are followed by cytochrome c release and caspase-dependent apoptotic nuclear events. Similarly, in NIH-OVCAR-3 cells, the OPA1 siRNA induces mitochondrial fragmentation and apoptosis, the latter being inhibited by Bcl2 overexpression. These results suggest that OPA1 is a major organizer of the mitochondrial inner membrane from which the maintenance of the cristae integrity depends. As loss of OPA1 commits cells to apoptosis without any other stimulus, we propose that OPA1 is involved in the cytochrome c sequestration and might be a target for mitochondrial apoptotic effectors. Our results also suggest that abnormal apoptosis is a possible pathophysiological process leading to the retinal ganglion cells degeneration in ADOA patients.
Olichon
Aurélien
A
Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, UMR 5088, Université Paul Sabatier, Bât. 4R3-B1, 118 route de Narbonne, F-31062 Toulouse cedex 04, France.
Baricault
Laurent
L
Gas
Nicole
N
Guillou
Emmanuelle
E
Valette
Annie
A
Belenguer
Pascale
P
Lenaers
Guy
G
D017209:Apoptosis; D003574:Cytochrome c Group / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology / Q000648:ultrastructure*; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000648:ultrastructure*; D014407:Tumor Cells, Cultured
D003574:Cytochrome c Group; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human