Mitochondrial Dysfunction and Oxidative Damage Linked in Study to a Genetic Corneal Disease

Mitochondrial Dysfunction and Oxidative Damage Linked in Study to a Genetic Corneal  Disease

Harvard Medical School researchers and colleagues have linked, for a first time, mitochondria dysfunction due to oxidative DNA damage in corneal endothelial cells to the development of Fuchs’ endothelial corneal dystrophy (FECD), the leading cause of age-related corneal edema requiring transplantation.

Their article, “Menadione-induced DNA damage leads to mitochondrial dysfunction and fragmentation during rosette formation in Fuchs Endothelial Corneal Dystrophy,” was published in the journal Antioxidants & Redox Signaling.

FECD, a genetic eye disease, is characterized by endothelial cell death that primarily affects the front surface of the eye (cornea), and progresses to blindness if left untreated. According to the Genetics Home Reference, FECD is a fairly common condition, affecting approximately 4 percent of the U.S. population over the age of 40. Currently, the only available and effective treatment to restore vision lost to FECD is corneal transplantation.

The research team investigated if an excess of mitochondrial reactive oxygen species (ROS) was responsible for the chronic oxidative DNA damage and mitochondrial dysfunction that  eventually causes corneal cell death. As endothelial cells do not go through cell division in humans, these cells in the cornea are prone to DNA damage through by-products of the mitochondrial respiratory chain, such as ROS, and through ultraviolet light. Moreover, the condition’s underlying genetic defects make the endothelial corneal cells even more susceptible to oxidative damage and mitochondrial dysfunction.

Using a compound called menadione to induce endogenous cellular oxidative stress, researches observed that FECD cells experienced an increase in mitochondrial and nuclear DNA damage, which correlated with loss of mitochondrial energy production. These events also led to mitochondrial fragmentation and molecular changes, such as cytochrome c release and apoptosis activation, that lead to the degeneration observed in FECD pathogenesis.

“This is a significant advancement in that process and moves us one step closer to our ultimate goal, which is to provide FECD patients with alternative and safer treatments options to transplantation,” the study’s principal investigator, Dr. Ula Jurkunas, MD, an associate professor of ophthalmology at Massachusetts Eye and Ear and Harvard Medical School, and co-director of the Ophthalmology Cornea Center of Excellence at Harvard, said in a news release.

The research team will now focus on the development of protective and anti-aging therapies for FECD patients.

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