Study co-author Jiajie Diao, PhD, working in his lab. Credit: Colleen Kelley/UC Marketing + Brand
Mitochondria, the “powerhouses of the cell,” are critical players in healthy cell homeostasis and function, and regularly undergo the processes of fission and fusion in order to maintain balance in the cell. Disruptions in these processes can lead to improperly functioning, oversized or undersized mitochondria, and such dysfunctions can lead to a number of mitochondrial diseases, including some forms of dementia and cancer. Researchers at the University of Cincinnati have now demonstrated how light can be used to induce fission in hyperfused mitochondria, raising the potential for new types of treatments for disease related to mitochondrial dysfunction.
The researchers work is based on optogenetics; the use of light-sensitive plant proteins to precisely control certain cell activities. The technique also relies on the use of contacts between mitochondria and lysosomes in order to set off the process of mitochondrial fission. The team fused photoactivatable heterodimerizers to the surfaces of mitochondria and lysosomes, so that the two organelles would be pulled toward each other when light was used to activate dimerization. Specifically, the researchers used cryptochrome (CRY2) and calcium and integrin-binding protein (CIB), which dimerize when irradiated by blue light. CRY2 was fused to mitochondria through fusion with GFP-labeled translocase of outer mitochondrial membrane 20 (TOM20) and CIB was fused to lysosomes with mCherry-labeled lysosomal associated membrane protein 1 (LAMP).
The team tested the optogenetic system in human stem cells with SLC25A46 deletion, a mutation that causes defects in mitochondrial fission. The researchers used structured illumination microscopy (SIM) to track the interactions between the mitochondria and lysosomes, and observed fragmentation of hyperfused mitochondria during blue light illumination. The team also found that the process also partially restored mitochondrial functions in the cells, improving oxidative phosphorylation (OXPHOS) and adenosine triphosphate (ATP) production. This study was published in Nature Communications.
“We would like to further expand the toolbox by introducing multicolor optogenetic systems to give us multiple ways to control how organelles behave and interact,” said study co-author Kai Zhang. “For instance, one color makes organelles come together, while the other color forces them apart. This way, we can precisely control their interactions.”
The team hopes to develop a system using light of longer wavelengths that can penetrate human tissue and make the technology more applicable for treating mitochondrial diseases. They also hope to eventually progress testing to animal models, and are also exploring the use of magnetic fields and acoustic vibrations instead of light to achieve similar results. Co-author Jiajie Diao believes similar technology could one day be used as a safer and more targeted way to treat cancer, for example, by using light-activated mitochondrial fission to cease mitochondrial function in cancer cells.