Abstract
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.
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Abbreviations
- AAV:
-
adenoassociated viral
- Drp1:
-
dynamin-related protein 1
- EDC:
-
ethyl-3-(3-dimethylaminopropyl) carbodiimide
- GFP:
-
green fluorescent protein
- IMM:
-
inner mitochondrial membrane
- IMS:
-
mitochondria intermembrane space
- Mfn1/2:
-
Mitofusins 1 and 2
- MPP+:
-
1-methyl-4-phenylpyridinium
- MPTP:
-
1-methyl-4-pheny-1,2,3,6-tetrahydropyridine
- OMM:
-
outer mitochondrial membrane
- OPA1:
-
Optic atrophy 1
- PARL:
-
presenilin-associated rhomboid-like protease
- PD:
-
Parkinson’s disease
- PINK1:
-
PTEN-induced putative kinase-1
- ROS:
-
reactive oxygen species
- SNpc:
-
substantia nigra pars compacta
- TH:
-
tyrosine hydroxylase
- TMPD:
-
N,N,N′,N′-tetramethyl-p-phenylenediamine
- TOM:
-
translocase of the mitochondrial outer membrane
- UT:
-
untreated
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Acknowledgements
We thank A Parent and E Pérez for their technical assistance, T Lindsten (University of Pennsylvania, USA) for providing Bak-deficient mice and A Strasser (The Walter and Eliza Hall Institute of Medical Research, Australia) for providing Bid-deficient mice. This work was supported by European Commission’s Marie Curie Excellence Grant and Marie Curie International Reintegration Grant (MV), Fundació la Caixa, Spain (MV), FIS-ISCIII, Spain (MV and CP), MICINN, Spain (MV), Ramón y Cajal Program (MICINN, to CP) and Miguel Servet Program (FIS-ISCIII, to JB).
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Ramonet, D., Perier, C., Recasens, A. et al. Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency. Cell Death Differ 20, 77–85 (2013). https://doi.org/10.1038/cdd.2012.95
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DOI: https://doi.org/10.1038/cdd.2012.95
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