UTA researchers identify proteins that may help stressed mitochondria to recover
Researchers at The University of Texas at Arlington have identified proteins in a signaling pathway in mammals that help mitochondria recover from stress. The discovery could pave the way to the development of new treatments for cancer and some neurological diseases.
Mitochondria are cell organs with multiple functions, including the production of cellular energy and the metabolism of amino acids and lipids, as well as the regulation of programmed cell death.
When mitochondria are stressed by disease, toxins or infection, a signaling pathway is created whereby a protein enters the cell nucleus and binds to specific DNA sequences to unlock genes that help repair the mitochondria. This pathway is called the mitochondrial unfolded protein response or UPRmt.
“We identified the protein ATFS-1 as the regulator of the UPRmt signaling pathway in C. elegans, a primitive worm that we study as it shares many characteristics with human biology. Recently ATF5 was found to encode a homologous protein in mammals, with similar mitochondrial and nuclear localization sequences,” said Mark Pellegrino, UTA assistant professor of biology and lead author of the mini-review study in the Journal of Biological Chemistry that included this research.
“The discovery of a clearer link between ATF5 and the UPRmt pathway in mammals could facilitate developing new therapies for diseases that result from mitochondrial dysfunction, including cancer,” he added.
The relationship between mitochondrial dysfunction and cancer is not homogeneous. In certain cancers, mitochondria are dysfunctional, while others display even enhanced functions. In these cases, mitochondrial recovery programs must be active that help support balanced mitochondrial function and consequently the growth and proliferation of tumors. Growing evidence suggests that the UPRmt may be one recovery pathway.
“While the links are complex, some researchers have found that inhibiting ATF5 increases tumor cell death while having little or no effect on healthy cells, which supports our targeting the UPRmt pathway for anti-cancer therapies,” Pellegrino said.
Pellegrino joined UTA last year from Memorial Sloan Kettering Cancer Center in New York with an $823,067 grant from The Cancer Prevention and Research Institute of Texas to study mitochondrial stress signaling in the context of cancer biology, part of which was used to fund this mini-review. His previous discovery that mitochondria are an important activator of innate immunity was published in the leading journal Nature in 2014.
“My aim is to use the pathway that mitochondria employ to repair themselves to develop therapeutics not only for cancer but for other pathologies linked to mitochondrial dysfunction, such as neurological disease, which is still relatively unexplored,” he added.
UTA has more than 30 faculty focused on cancer research and registered more than $4 million in research expenditures for cancer in the academic year 2016-2017. Cancer research is an integral part of the University’s focus on Health and the Human Condition, one of the four guiding themes put forth in UTA’s Strategic Plan Bold Solutions|Global Impact.