Studies implicate photoreceptor mitochondria as initiator in uveitis-associated vision loss

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Mitochondrial oxidative stress induced by translocation of inducible nitric oxide synthetase (iNOS) from the cytosol into the photoreceptor mitochondria appears to be a primary event leading to photoreceptor damage in experimental autoimmune uveitis (EAU), said Narsing A. Rao, MD, professor of ophthalmology, and director, ophthalmic pathology laboratory and uveitis service, University of Southern California, Los Angeles.

Mitochondrial oxidative stress induced by translocation of inducible nitric oxide synthetase (iNOS) from the cytosol into the photoreceptor mitochondria appears to be a primary event leading to photoreceptor damage in experimental autoimmune uveitis (EAU), said Narsing A. Rao, MD, professor of ophthalmology, and director, ophthalmic pathology laboratory and uveitis service, University of Southern California, Los Angeles.

"Epidemiologic studies show that complications of uveitis, particularly photoreceptor degeneration, are an important cause of vision loss," said Dr. Rao, who spoke during a symposium on mitochondrial oxidative stress in the visual system. "Based on previous investigations in EAU, the photoreceptor damage was thought to be caused by infiltrating macrophages releasing damaging oxidants.

"However, contradicting that dogma, we previously showed evidence that photoreceptor mitochondrial stress was present several days prior to infiltration of the phagocytic cells," Dr. Rao said. "Further studies now support the concept that the photoreceptor mitochondria are responsible for initiating the irreversible retinal damage occurring in EAU."

EAU, an animal model of uveitis that closely mimics the human disease, is created by immunizing Lewis rats with retinal soluble protein S-antigen. Dr. Rao described the findings from a series of EAU studies using wild type and iNOS knockout animals that were performed to characterize the cellular and molecular events occurring early after immunization.

Based on those experiments, Dr. Rao and colleagues proposed the following sequence to describe the pathway leading to photoreceptor damage in EAU.

"We believe that following immunization with the retinal antigen, a few activated T-cells infiltrate the retina where they induce expression of the TNF-alpha receptor and generate increases in TNF-alpha and other cytokines known to increase iNOS," Dr. Rao explained. "The upregulated iNOS subsequently translocates to the photoreceptor mitochondria and leads to mitochondrial oxidative stress and damage, including protein nitration, lipid peroxidation, and DNA damage, that ultimately culminates in photoreceptor cell apoptosis and vision loss."

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