Abstract
Optic atrophy resulting from retinal ganglion cell (RGC) degeneration is a prominent ocular manifestation of mitochondrial dysfunction. Although transgenic mice lacking the mitochondrial complex I accessory subunit NDUFS4 develop early-onset optic atrophy, severe systemic mitochondrial dysfunction leads to very early death and makes this mouse line impractical for studying the pathobiology of mitochondrial optic neuropathies. Theoretically, RGC-specific inactivation of ndufs4 would allow characterization of RGC degeneration over a longer time course, provided that RGC death from mitochondrial dysfunction is a cell-autonomous process. We demonstrate that the vesicular glutamate transporter VGLUT2 may be exploited to drive robust Cre recombinase expression in RGCs without any expression observed in directly neighboring retinal cell types. Deletion of ndufs4 in RGCs resulted in reduced expression of NDUFS4 protein within the optic nerves of Vglut2-Cre;ndufs4loxP/loxP mice. RGC degeneration in Vglut2-Cre;ndufs4loxP/loxP retinas commenced around postnatal day 45 (P45) and progressed to loss of two-thirds of RGCs by P90, confirming that intrinsic complex I dysfunction is sufficient to induce RGC death. The rapidly-developing optic atrophy makes the Vglut2-Cre;ndufs4loxP/loxP mouse line a promising preclinical model for testing therapies for currently untreatable mitochondrial optic neuropathies such as Leber Hereditary Optic Neuropathy.
Highlights
Mitochondrial dysfunction contributes to vision loss in many retinal and optic nerve d isorders[1,2,3], with a small but important subset comprised by heritable mitochondrial d iseases[4]
We report that conditional deletion of ndufs[4] in Vglut2-expressing neurons results in progressive loss of retinal ganglion cell (RGC) somas and axons, with associated neuroinflammation of the inner retina
By using a tdTomato reporter to assess the extent of Vglut2-driven Cre expression in other retinal neurons, we have addressed the lingering question of whether or not RGC degeneration in the setting of complex I deficiency is a cell-autonomous process
Summary
Mitochondrial dysfunction contributes to vision loss in many retinal and optic nerve d isorders[1,2,3], with a small but important subset comprised by heritable mitochondrial d iseases[4]. With a prevalence of 1:30,000 to 1:50,000, LHON is likely the most common human disease with a mitochondrial pattern of inheritance[6,7,8] It is caused by hypomorphic missense mutations in mitochondrial DNA (mtDNA) encoding subunits of respiratory complex I (NADH:ubiquinone oxidoreductase). Because the loss of function resulting from the mtDNA mutations associated with LHON is usually relatively mild, homoplasmy of the mutations is frequently required for optic neuropathy to d evelop[10,11,12], and the remaining tissues of the body are usually ( not invariably) spared from p athology[13,14] This is in stark contrast to the severe systemic mitochondrial disease Leigh syndrome, some forms of which develop from mutations affecting complex I s ubunits[15]. We used a transgenic mouse line expressing Cre recombinase within a subset of glutamatergic neurons to test the hypothesis that RGC degeneration in complex I deficiency is a cell-autonomous process and to characterize the progression of optic atrophy over multiple time points
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
