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

By A. Olichon, L. Baricault, N. Gas, E. Guillou, A. Valette, P. Belenguer, G. Lenaers. Journal of Biological Chemistry, 2003

1,184 citations recorded by the source corpus.

OPA1 encodes a large GTPase related to dynamins, anchored to the mitochondrial cristae inner membrane, facing the intermembrane space. OPA1haplo-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 cytochromec 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4686dd912388ea7a06634896daa9b180612eda8b

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Citations in the corpus

Fission and selective fusion govern mitochondrial segregation and elimination by autophagy (2008, background): “Conversely, Dcm is influenced when fusion is inhibited (Olichon et al, 2003; Chen et al, 2005), suggesting that reduced fusion capacity could be either the cause or the result of Dcm depolarization.”
Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. (2004, background): “Down-regulation of Opa1 expression in cells by RNAi results in spontaneous cell apoptosis (Olichon et al., 2003), suggesting that the promotion of mitochondrial fusion by wild-type levels of Opa1 normally protects cells from apoptosis.”
OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L (2007, neutral): “OPA1 is associated with the inner membrane and protects cells from apoptosis by regulating inner membrane dynamics (Olichon et al., 2003; Frezza et al., 2006).”
Mitochondrial dynamics and apoptosis. (2008, background): “Loss of OPA1 induces spontaneous apoptosis of cells, providing another important link between apoptosis and mitochondrial morphogenesis (Olichon et al. 2003).”
Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells (2010, background): “…mitochondrial fragmentation is suppressed by knockdown of either Drp1 or Mff but not hFis1 Opa1 knockdown causes extensive mitochondrial fragmentation and cristae disorganization with increased sensitivity to apoptotic stimuli (Olichon et al., 2003; Lee et al., 2004; Frezza et al., 2006).”
The Interplay Between Mitochondrial Dynamics and Mitophagy (2011, background): “Opa1 is a protein with multiple isoforms that is localized in the inner membrane and in the intermembrane space of mitochondria (33, 78).”
The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice (2009, result): “This is in sharp contrast to the dramatic alterations in the cristae membrane structures observed in mitochondria defective in membrane fusion (Olichon et al., 2003; Griparic et al., 2004; Chen et al., 2007).”
Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex (2010, background): “Although the precise reason for mitochondrial fusion remains unclear, interruption of mitochondrial fusion (via loss of Opa1 or Mfn1/2) leads to loss of mitochondrial potential and diminished oxidative phosphorylation, indicating it is critical for maintaining mitochondrial function (Olichon et al.,”
Dynamics of mitochondrial morphology in healthy cells and during apoptosis (2003, result): “release of cytochrome c from mitochondria to the cytosol and subsequent induction of apoptotic cell death.(74) Notably, in addition to the remodeling of mitochondrial cristae, depletion of OPA1 results in the fragmentation of the mitochondrial network, similar in morphology to that observed in Dmgm1”
Mechanisms of mitochondrial fission and fusion. (2013, background): “In mammals, loss of both inner and outer membrane fusion proteins promotes cytochrome c release during apoptosis, but the effects of losing the inner membrane fusion protein Opa1 are much more severe (Olichon et al. 2003; Arnoult et al. 2005).”