PASADENA, Calif., Jan. 29, 2024 (GLOBE NEWSWIRE) -- Doheny Eye Institute, one of the nation’s leading vision research institutions, is pleased to announce the publication of important new findings in the highly respected scientific journal Proceedings of the National Academy of Science, U.S.A.
Doheny Eye Institute scientists, working with colleagues at UCLA and University of Texas, have shown how a single gene mutation in the enzyme complex that produces the energy used by cells causes a sudden, blinding disease called Leber’s Hereditary Optic Neuropathy (LHON). The mutation affects the cells’ tiny mitochondria, miniature power stations that generate the energy molecules called ‘ATP,’ that all cells of the body require to do their jobs and stay alive. The mystery of how LHON causes blindness is now illuminated: the mutation causes alterations in quantum electron tunneling. Quantum tunneling is an amazing process, totally unlike classical chemistry, that enables elementary particles, like electrons, to penetrate through energy barriers. What is now shown is that quantum tunneling is likely central to many biological reactions and may be key in explaining other human diseases.
Dr. Alfredo Sadun, renowned ophthalmologist and global expert on this disease, and biophysicist Dr. Steven Barnes, both of Doheny Eye Institute and UCLA’s Department of Ophthalmology, tapped the expertise of UCLA Department of Chemistry’s Drs. Anastassia Alexandrova and Jack Fuller, to address the disease using state-of-the-art computational chemistry tools. This maternally-inherited genetic disorder typically waits for two decades before it strikes its victims, causing severe loss of vision or blindness, usually in young adult men, and to a lesser extent women, in their twenties.
In a commentary published in the same journal as the study, Prof. P.J. Burke of UC Irvine praised the authors for this important step in explaining how this DNA defect causes blindness. Describing the work’s importance, Burke states that it has “broad significance as a model for dissecting the link between energy, health, and life.”
Members of the team previously showed that this disease kills the eye’s retinal ganglion cells (RGCs) not by causing poor energy production, but rather by producing ‘reactive oxygen species,’ or ROS, normal cellular molecules that when over-produced seriously impair cell protein function. In LHON, these damaging ROS are an unnoticed problem that waits decades before damage suddenly exceeds a threshold, triggering the death of RGCs, neurons that transmit electrical signals coding patterns of light from the eye to the brain. In order to determine the origin of the ROS, the group examined how the single genetic mutation affects a key subsection of the cell’s mitochondria with a single amino acid swap. It is in this subsection, called Complex I, that the mobility of the energy-trafficking molecule CoQ10 is seriously impaired. CoQ10, getting into and out of a tight-fitting channel in Complex I, defines the rate of the quantum tunneling of electrons that play a central role for generating ATP.
Powerful Molecular Dynamics simulations were performed using the National Supercomputer network to analyze the impact of the single amino acid swap from alanine to threonine in Complex I on the mobility of CoQ10 at different speeds via calculation of the positions and free energy of the molecules. They found that CoQ10 exits the mutated channel a billion times slower than it would in a normal channel. The continuous supply of electrons to Complex I, now having nowhere to go, produces excessive rates of electron backup and spillage that generates ROS. This conclusion supports earlier observations that neurons with models of LHON produce near normal amounts of ATP but high levels of ROS, which facilitate RGC death.
Link to the full article: https://pubmed.ncbi.nlm.nih.gov/37733737/
About Doheny Eye Institute
Doheny Eye Institute is one of the nation’s leading vision research institutions with a history dating back over 75 years. Doheny scientists and clinician-scientists remain at the forefront of vision science investigating how retinal neurons function in health and in diseases, such as diabetic retinopathy, optic neuropathies, uveitis, age-related macular degeneration, and the use of artificial intelligence for improved diagnosis of ocular diseases.
Since 2013, the Doheny and UCLA Stein Eye Institute affiliation combines the strength, reputation, and distinction of two of the nation’s top eye institutions to advance vision research, education, and patient care in Southern California. Together, Doheny Eye Institute and UCLA Stein Eye Institute are ranked in the Top 5 vision centers in the country by U.S. News & World Report.
For more information visit www.Doheny.org.
Contact:
Molly Ann Woods
310-717-0955
mwoods@doheny.org
