In a study using cells grown in a lab, Johns Hopkins Medicine researchers who specialize in aging report that they have successfully delivered a common blood pressure drug directly to the inner membrane of mitochondria, the “power stations” in cells of humans, animals, plants and more. other objects.
Developing ways to target these energy-producing parts of the cell to deliver drugs has long been a goal of researchers because mitochondria drive, control, or play a role in nearly every biological process, including normal cell death and aging. Alterations or decreases in the activity of mitochondria and pathways are closely aligned with decreased organ function and impairment. But due to the double-membrane structure of the mitochondria, scientists have found it difficult to make the drug molecules penetrate the inner membrane and reach the basic functions of the organelles.
The new study, described in the August 4 issue of PNAS . Connectreports a method that essentially hijacks a system already used by mitochondria to transport oxygen and other chemicals to the inner membrane.
Our study shows that we can use the body’s natural mitochondrial transport system to deliver drugs more accurately. “
Peter Abader, MD, assistant professor of geriatrics and geriatrics, Johns Hopkins University School of Medicine
For the study, the researchers synthesized three naturally occurring transport proteins that interact with mitochondria. Then they combined a commonly prescribed blood pressure drug (losartan) with each of these three proteins to determine which had the highest success rate in penetrating the inner mitochondrial membrane. These fused proteins, termed mtLOS1, mtLOS2 and mtLOS3, when introduced into cells cultured in vitro in separate experiments, were able to transport the drug directly into the mitochondria at a much higher concentration than was possible with free losartan that did not fuse with the transport protein. This can be seen under a microscope using fluorine.
In a proof of concept trial, the researchers also tested a “blended” version of mtLOS, which was not able to penetrate the inner membrane.
More research is needed, Abadir says, but the goal is to use mtLOS or other natural transport pathways to deliver drugs that directly and effectively target biochemical imbalances and losses associated with chronic inflammation and organ dysfunction characteristic of aging and many disorders.
“We know that people age in part because of the deterioration of mitochondria, and scientists are trying to introduce therapies directly into the organelle to counteract this deterioration,” Abadir says. “This is yet another attempt to deliver compounds using the body’s natural systems, which may significantly reduce negative side effects in the short and long term.”
Han Wang, Jeremy Walston, Peter Abader, and Ran Lin have filed two patents based on this research. All other authors declared no conflict of interest.
Other scientists who contributed to this research include Judd Phillips, Ran Lin, Andrew Cheetham, David Stern, Yukang Li, Yuzhu Wang, Han Wang, David Rainey, Honggang Cui, and Jeremy Walston of Johns Hopkins University.
The research was funded by the Johns Hopkins Center for the Independence of Older Americans, the National Institute on Aging-National Institutes of Health, the Johns Hopkins University School of Medicine Synergy Award, the Nathan W. and Margaret T. and Nathan Schock Scholar in Aging.
Philip, J.M., et al. (2022) Nature-inspired delivery of mitochondrial-targeted angiotensin receptor blockers. PNAS Nexus. doi.org/10.1093/pnasnexus/pgac147.