OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis.
In most eucaryote cells, release of apoptotic proteins from mitochondria involves fission of the mitochondrial network and drastic remodelling of the cristae structures. The intramitochondrial dynamin OPA1, as a potential central actor of these processes, exists as eight isoforms resulting from the alternate splicing combinations of exons (Ex) 4, 4b and 5b, which functions remain undetermined. Here, we show that Ex4 that is conserved throughout evolution confers functions to OPA1 involved in the maintenance of the DeltaPsi(m) and in the fusion of the mitochondrial network. Conversely, Ex4b and Ex5b, which are vertebrate specific, define a function involved in cytochrome c release, an apoptotic process also restricted to vertebrates. The drastic changes of OPA1 variant abundance in different organs suggest that nuclear splicing can control mitochondrial dynamic fate and susceptibility to apoptosis and pathologies.
Olichon
A
A
Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, CNRS UMR 5088, Université Paul Sabatier, 118 route de Narbonne, Toulouse Cedex, France.
Elachouri
G
G
Baricault
L
L
Delettre
C
C
Belenguer
P
P
Lenaers
G
G
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D019143:Evolution, Molecular; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000378:metabolism*; D006367:HeLa Cells / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D051336:Mitochondrial Membranes / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000235:genetics; D020539:Sequence Analysis, Protein; D014407:Tumor Cells, Cultured; D015003:Yeasts / Q000378:metabolism*
D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human