Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex i deficiency
Cell Death Differ. 2012-08-03; 20(1): 77-85
DOI: 10.1038/cdd.2012.95
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Mitochondrial complex I dysfunction has long been associated with Parkinson’s
disease (PD). Recent evidence suggests that mitochondrial involvement in PD may
extend beyond a sole respiratory deficit and also include perturbations in
mitochondrial fusion/fission or ultrastructure. Whether and how alterations in
mitochondrial dynamics may relate to the known complex I defects in PD is
unclear. Optic atrophy 1 (OPA1), a dynamin-related GTPase of the inner
mitochondrial membrane, participates in mitochondrial fusion and apoptotic
mitochondrial cristae remodeling. Here we show that complex I inhibition by
parkinsonian neurotoxins leads to an oxidative-dependent disruption of OPA1
oligomeric complexes that normally keep mitochondrial cristae junctions tight. As
a consequence, affected mitochondria exhibit major structural abnormalities,
including cristae disintegration, loss of matrix density and swelling. These
changes are not accompanied by mitochondrial fission but a mobilization of
cytochrome c from cristae to intermembrane space, thereby lowering the threshold
for activation of mitochondria-dependent apoptosis by cell death agonists in
compromised neurons. All these pathogenic changes, including mitochondrial
structural remodeling and dopaminergic neurodegeneration, are abrogated by OPA1
overexpression, both in vitro and in vivo. Our results identify OPA1 as molecular
link between complex I deficiency and alterations in mitochondrial dynamics
machinery and point to OPA1 as a novel therapeutic target for complex I
cytopathies, such as PD.