Photoreceptors in a Mouse Model of Leigh Syndrome are Capable of Normal Light-Evoked Signaling.
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Mitochondrial dysfunction is an important cause of heritable vision loss. Mutations affecting mitochondrial bioenergetics may lead to isolated vision loss or life-threatening systemic disease, depending on a mutation's severity. Primary optic nerve atrophy resulting from death of retinal ganglion cells is the most prominent ocular manifestation of mitochondrial disease. However, dysfunction of other retinal cell types has also been described, sometimes leading to a loss of photoreceptors and retinal pigment epithelium that manifests clinically as pigmentary retinopathy. A popular mouse model of mitochondrial disease that lacks NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4), a subunit of mitochondrial complex I, phenocopies many traits of the human disease Leigh syndrome, including the development of optic atrophy. It has also been reported that ndufs4-/- mice display diminished light responses at the level of photoreceptors or bipolar cells. By conducting electroretinography (ERG) recordings in live ndufs4-/- mice, we now demonstrate that this defect occurs at the level of retinal photoreceptors. We found that this deficit does not arise from retinal developmental anomalies, photoreceptor degeneration, or impaired regeneration of visual pigment. Strikingly, the impairment of ndufs4-/- photoreceptor function was not observed in ex vivo ERG recordings from isolated retinas, indicating that photoreceptors with complex I deficiency are intrinsically capable of normal signaling. The difference in electrophysiological phenotypes in vivo and ex vivo suggests that the energy deprivation associated with severe mitochondrial impairment in the outer retina renders ndufs4-/- photoreceptors unable to maintain the homeostatic conditions required to operate at their normal capacity.
SubjectNADH:ubiquinone oxidoreductase subunit S4 (NDUFS4)
Published Version (Please cite this version)10.1074/jbc.ra119.007945
Publication InfoGospe, Sidney; Arshavsky, Vadim; Travis, Amanda M; Kolesnikov, Alexander V; Klingeborn, Mikael; Wang, Luyu; & Kefalov, Vladimir J (2019). Photoreceptors in a Mouse Model of Leigh Syndrome are Capable of Normal Light-Evoked Signaling. The Journal of biological chemistry. pp. jbc.RA119.007945-jbc.RA119.007945. 10.1074/jbc.ra119.007945. Retrieved from https://hdl.handle.net/10161/19166.
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Helena Rubinstein Foundation Professor of Ophthalmology
Research conducted in our laboratory is dedicated to understanding how vision is performed on the molecular level. Our most mature direction addresses the function of rod and cone photoreceptors, which are sensory neurons responsible for the detection and primary processing of information entering the eye in the form of photons. Photoreceptors respond to capturing photons by generating electrical signals transmitted to the secondary neurons in the retina and, ultimately, to the brain. Our wor
Assistant Professor of Ophthalmology
Dr. Gospe joined Duke Ophthalmology on August 1, 2017 following his neuro-ophthalmology fellowship training at Duke. His research interests center on developing novel genetic mouse models of severe mitochondrial dysfunction in retinal ganglion cells (RGCs) and other retinal neurons in order to recapitulate the RGC degeneration seen in human optic neuropathies and the poorly understood pigmentary retinopathy that may accompany these diseases. Mitochondria are the powerhouse o
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