Light-activated protein may help normalize dysfunction in cells, study shows

New research from the University of Cincinnati is showing early indications that light could be used as a treatment for certain ailments, including cancer.

Researchers from UC, University of Illinois Urbana-Champaign and University at Buffalo published the results of their study showing light-activated proteins can help normalize dysfunction in cells in the journal. Nature Communication July 25.

Research findings

Research centers on the function of mitochondria, the organelles in cells that act as the cell’s “power generator” and source of energy. Organelles are small specialized structures that perform various jobs in the cell.

Jiajie Diao, PhD, one of the study’s authors, says hundreds of mitochondria are constantly coming together (a process called fusion) and dividing into smaller pieces (a process called fission) to keep them in balance in healthy cells. But when mitochondria don’t function properly, an imbalance of these fission and fusion processes occurs.

This imbalance can lead to a number of mitochondrial diseases, including neurodegenerative diseases such as dementia and certain cancers.

Diao said previous research had found that other organelles within cells called lysosomes could play a role in mitochondrial division. When mitochondria come into contact with lysosomes, they can act like scissors and cut the mitochondria into smaller pieces.

Current research focuses on initiating the fission process by uniting lysosomes and mitochondria in cells. This is achieved using a technique known as optogenetics, which can precisely control the function of certain cells using light.

“Many proteins in plants are light-sensitive, telling plants whether it’s day or night. Optogenetics borrows these light-sensitive proteins from plants and uses them in animal cells,” says Kai Zhang, PhD, professor at the University of Illinois Urbana-author of the campaign and study, who developed optogenetic tools for controlling mitochondria and lysosomes with blue light. “By attaching these proteins to organelles, one can use light to control interactions between them, such as mitochondria and lysosomes shown in this work,” he said.

The researchers attached two separate proteins to the mitochondria and lysosomes inside the stem cells. When stimulated by blue light, the proteins naturally bind to each other to form one new protein, which also brings mitochondria and lysosomes into contact. Once they are fused, lysosomes can cut through the mitochondria, achieving fission.

We found that it can restore mitochondrial function. Some cells can even return to normal. This proves that using just a few simple light stimuli, we can at least partially restore the mitochondrial function of the cell.”

Jiajie Diao, PhD, professor in the Department of Cancer Biology at UC School of Medicine and member of the University of Cincinnati . Cancer Center

Diao said the technique could be particularly useful for patients with very large mitochondria that need to be divided into smaller parts to achieve normal cell function. The technique can also be targeted at cancer cells, constantly separating the mitochondria into smaller and smaller pieces until they can no longer function.

“Eventually cancer cells will die because mitochondria are the energy,” Diao said. “Without normal functional mitochondria, all cancer cells would be killed.”

Because the protein is activated by light, Diao says it allows a more targeted approach to specific cells. Only cells exposed to light are affected, meaning nearby healthy cells do not have mitochondria that are out of balance through this technique.

There are currently other processes that can be used to induce mitochondrial division, but Diao said the optogenetic method is safer because it doesn’t involve chemicals or toxic agents.

“What we have is actually a natural process, we just make it go faster,” Diao said. “So it’s not like chemicals or therapy or radiotherapy where you need to reduce the side effects.”

The next step

Diao said his team was already working on using a similar technique to induce fusion to address the problem when mitochondria are out of balance because they are too small and don’t fit together properly in cells.

Further research from Zhang’s lab will also include the development of a new optogenetic system that works with different colors of light, including green, red and infrared, as longer wavelengths will be required to penetrate human tissue.

“We wanted to further expand the toolbox by introducing a multicolored optogenetic system to give us multiple ways to control how organelles behave and interact,” Zhang said. “For example, one color brings organelles together, while another color forces them apart. This way, we can control their interactions precisely.”

From current research using human stem cells, the team hopes to move forward to testing its efficacy using animal models on the way to eventually testing the technique in humans through clinical trials. At the same time, Diao said another research group is studying the use of magnetic fields and acoustic vibrations instead of light to achieve similar results.

Source:

Journal reference:

Qiu, K., et al. (2022) Light-activated mitochondrial cleavage via optogenetic control of the mitochondria-lysosomal contact. Nature Communication. doi.org/10.1038/s41467-022-31970-5.

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