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G. Lenaers, C. Soukkarieh, C. Delettre, G. ElAchouri, A. Olichon, C. P. Hamel; Functional Dichotomy of the Mitochondrial Dynamin Opa1: Patho-Physiological Consequences for Optic Nerve Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1540.
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We address here the correlations between Optic Nerve degeneration, Retinal Ganglion Cell mitochondrial network singularities and the functions of the pleiotropic mitochondrial dynamin OPA1, which is encoded by the gene responsible for the most common form of Dominant Optic Atrophy (MIM165500) an Inherited Optic Neuropathy.
Overexpression and silencing of OPA1 variants in HeLa cells associated to phenotype characterization with emphasis on mitochondrial functions. Immunohistology and electron microscopy performed on mouse retina, optic nerve and optic tracts, using OPA1 and ATP synthase antibodies.
We evidenced that OPA1 isoforms associated to Ex4 are involved in mitochondrial network dynamic and maintenance of ATP synthesis, while isoforms associated to Ex4b and 5b are specifically involved in the control of cytochrome c release during apoptosis. Therefore patho-physiological mechanisms due to OPA1 dysfunction are either susceptibility to apoptosis or uneven mitochondrial and energetic distribution. In mouse, OPA1 is early expressed in the neuroretina, before finding active mitochondria. After birth, OPA1 is ubiquitously and highly expressed in active mitochondria in all retinal cell layers including RGC cell bodies and axons. After the lamina cribosa, OPA1 as well as mitochondria become less abundant in the optic nerve and barely detectable in the optic chiasma, optic tracts and in the coliculus. Most surprisingly, at the lamina cribosa, where axons become myelinated, mitochondria undergo major membrane remodelling with lengthening of their structure and drastic cristae reorganization, suggesting a critical involvement of OPA1 in this process.
Together, these data point to the patho-physiological hypothesis for optic nerve degeneration, emphasizing RGC susceptibility to pro-apoptotic stimuli and RGC energetic requirements for transduction of visual information, and situate mitochondria at the centre of the function and dysfunction of optic nerve.
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