OPA1 cleavage depends on decreased mitochondrial ATP level and bivalent metals.
OPA1, an intra-mitochondrial dynamin GTPase, is a key actor of outer and inner mitochondrial membrane dynamic. OPA1 amino-terminal cleavage by PARL and m-AAA proteases was recently proposed to participate to the mitochondrial network dynamic in a DeltaPsi(m)-dependent way, and to apoptosis. Here, by an in vitro approach combining the use of purified mitochondrial fractions and mitochondrial targeting drugs, we intended to identify the central stimulus responsible for OPA1 cleavage. We confirm that apoptosis induction and PTPore opening, as well as DeltaPsi(m) dissipation induce OPA1 cleavage. Nevertheless, our experiments evidenced that decreased mitochondrial ATP levels, either generated by apoptosis induction, DeltaPsi(m) dissipation or inhibition of ATP synthase, is the common and crucial stimulus that controls OPA1 processing. In addition, we report that ectopic iron addition activates OPA1 cleavage, whereas zinc inhibits this process. These results suggest that the ATP-dependent OPA1 processing plays a central role in correlating the energetic metabolism to mitochondrial dynamic and might be involved in the pathophysiology of diseases associated to excess of iron or depletion of zinc and ATP.
Baricault
Laurent
L
LBCMCP, CNRS, Université de Toulouse, France. baricaul@cict.fr
Ségui
Bruno
B
Guégand
Laurie
L
Olichon
Aurélien
A
Valette
Annie
A
Larminat
Florence
F
Lenaers
Guy
G
D000255:Adenosine Triphosphate / Q000032:analysis / Q000172:deficiency; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002413:Cations, Divalent / Q000032:analysis / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000032:analysis / Q000378:metabolism*; D019169:Jurkat Cells; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000032:analysis / Q000378:metabolism*