Loss of OPA1 Perturbates the Mitochondrial Inner Membrane Structure and Integrity, Leading to Cytochrome c Release and Apoptosis

Abstract

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 caspasedependent 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.

Mitochondria and cancer: is there a morphological connection?

“…Firstly, loss of Opa1 expression has been reported to trigger apoptosis by inducing such intramitochondrial remodelling (Olichon et al, 2003). Secondly, Bik, a BH3-only protein present on the ER, has been shown to induce Drp1-dependent remodelling of the cristae compartment (Germain et al, 2005).…”

“…The Mitofusins appear to play distinct roles in fusion and the Mfn1 presumably works together with Opa1, a GTPase of the inner mitochondrial membrane (IMM) to promote fusion (Cipolat et al, 2004). While its exact function remains unclear, Opa1 seems also involved in further intramitochondrial remodelling (Olichon et al, 2003). Mitofilin is another protein that has recently been involved in cristae morphology (John et al, 2005).…”

OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis

“…8 In addition, BH3-only proapoptotic proteins, exemplified by tBid and Bik, might act directly on the IMM structure, although their intramitochondrial target remains unknown. 3,9 Further crosstalk between the OMM and the IMM is exemplified by the OMM fission and fusion regulation by the mitochondrial membrane potential (DC m ) 10 and structural integrity 11 and by interaction between OPA1 and Mfn1. 12 The IMM forms, an architecturally complex structure, that has been reconsidered recently in the light of tomography analysis associated to transmission electron microscopy (TEM).…”

“…We and others have shown that OPA1 is a good candidate for the regulation of the cristae structure in the mitochondria. 11,14 Indeed, downregulation of OPA1 affect the IMM structure and integrity, leading to respiration defects and DC m loss, fission of the mitochondrial network, impairment of growth and apoptosis 11,[14][15][16][17][18] and OPA1 overexpression protects from cyt c mobilization by tightening cristae junctions. 14 OPA1 is also partially associated to the OMM, on its IMS side, where it might interact with Mfn1 to promote fusion of the mitochondrial network, or maintain a physical link between the OMM and IMM.…”

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

“…This is accompanied by organelle dysfunction and cytochrome c release and interestingly by changes in mitochondrial ultrastructure. 60 These results raised the possibility that Opa1 could as a matter of fact participate in the biogenesis of the cristae and regulate the cristae remodelling pathway.…”