Alfredo A. Sadun, MD, PhD, discusses research targeting LHON

In a recent conversation with Ophthalmology Times, Alfredo A. Sadun, MD, PhD, chief at Doheny Eye Center – UCLA, discusses a paper titled Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

The paper has been nominated for a Cozzarelli Prize, which is awarded annually to 6 research teams whose PNAS articles have made outstanding contributions to their field. Each team represents one of the 6 classes of the National Academy of Sciences (NAS): Physical and Mathematical Sciences; Biological Sciences; Engineering and Applied Sciences; Biomedical Sciences; Behavioral and Social Sciences; and Applied Biological, Agricultural, and Environmental Sciences.

“Yes, we were very proud of that paper,” Sadun said. “It came out in the Journal of the National Academy of Sciences a couple of months ago.”

Sadun is the senior author on the article.

“I’ve spent my life studying Leber's hereditary optic neuropathy, or LHON,” he explained in the conversation.“And it got into some really deep biology and then physics and then quantum mechanics as part of the answer. It's really neat to do something so fundamental and basic with implications that probably go beyond this disease, and go to how the chemistry of life works.”

Scientists at Doheny Eye Institute, in a collaboration with colleagues at UCLA and the University of Texas, have shown how a single gene mutation in the enzyme complex that produces the energy used by cells causes LHON.

According to a Doheny Eye Institute news release, the researchers found 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.¹

Sadun worked with biophysicist Steven Barnes, PhD, both of Doheny Eye Institute and UCLA’s Department of Ophthalmology, tapped the expertise of UCLA Department of Chemistry’s Anastassia Alexandrova, PhD, and Jack Fuller, PhD, to address the disease using state-of-the-art computational chemistry tools.

Sadun pointed out that one mystery of the disease is why it strikes primarily young men in their 20s.

“The patient usually diagnosed with the disease is usually a health young person in his early 20s and thought everything was fine. It is a mysterious disease in many ways,” he told Ophthalmology Times. “There is no effective treatment in the United States. There is no FDA-approved treatment.”

Sadun noted that Idebenone has been approved by the European Medicines Agency for use in LHON.

According to scientists, the 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.

According to the news release, the scientists 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 team of scientists looked at 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 generate 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.

“We used molecular dynamics and FEP simulations to elucidate the mechanistic impact of the m.3460G>A mutation on the function of the ND1 protein, leading to Leber’s hereditary optic neuropathy,” the researchers concluded. “These simulations show how, in the case of the m.3460G>A mutation, the alanine to threonine substitution at position 52 leads to the extended CH3 and an additional OH in the path of the CoQ10. “

According to the study, this creates a kinetic hindrance for CoQ10 to pass through the binding channel. The scientists noted the thermal energy required to move the CoQ10 out of the channel is estimated about 50 kT, far too much to allow diffusion to occur at appreciable rates.¹

“Failed electron transfer will lead to electron spillage and ROS production at the proximal end of the FeS cluster series,” the scientists concluded. “ROS are a known cause of the blindness from Leber’s hereditary optic neuropathy, and this work thus links the molecular origin of ROS overproduction to the disease process.”

Reference:

1. Fuller JT 3rd, Barnes S, Sadun LA, Ajmera P, Alexandrova AN, Sadun AA. Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy. Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2304884120. doi: 10.1073/pnas.2304884120. Epub 2023 Sep 21. PMID: 37733737; PMCID: PMC10523484.