A new University of Michigan study outlines the discovery of a protein that acts as a powerful protectant against free radicals. Ironically, the protein is activated by excessive free radicals. Human mutations of the gene for this protein are previously known to cause a rare, neurodegenerative disease.
Lysosomes, which comprise the cell’s recycling center, are crucial for cleaning up injured and dying parts of the cells, said lead researcher Haoxing Xu, U-M associate professor of molecular, cellular and developmental biology.
When lysosomes “sense” an overload of free radicals, they activate a calcium channel on their membranes. This triggers the expression of many genes and the production of more and stronger lysosomes, which rev into overdrive to rid the damaged parts of the cells.
Free radicals are guilty in the aging process, Xu said.
The red dye in the cell show healthy mitochondria in a healthy cell. Images courtesy: Haoxing Xu
“If we have chemical compounds that can directly activate this channel, we can lower the oxidative stress in aging and other diseases,” he said. “The result will be that cell damage and free radical levels could be reduced, and one can possibly slow down aging.”
How does the body tell itself that there are too many free radicals so that they can be reduced or removed? His study tells us how it’s done, Xu said.
“Nature is really cool,” said. “The janitor of the cell, the lysosome, has this radical-sensing ability.”
Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes ‘host’ multiple stress-sensing mechanisms that trigger the coordinated biogenesis of autophagosomes and lysosomes. For example, transcription factor (TF)EB, which regulates autophagy and lysosome biogenesis, is activated following the inhibition of mTOR, a lysosome-localized nutrient sensor. Here we show that reactive oxygen species (ROS) activate TFEB via a lysosomal Ca2+-dependent mechanism independent of mTOR. Exogenous oxidants or increasing mitochondrial ROS levels directly and specifically activate lysosomal TRPML1 channels, inducing lysosomal Ca2+ release. This activation triggers calcineurin-dependent TFEB-nuclear translocation, autophagy induction and lysosome biogenesis. When TRPML1 is genetically inactivated or pharmacologically inhibited, clearance of damaged mitochondria and removal of excess ROS are blocked. Furthermore, TRPML1’s ROS sensitivity is specifically required for lysosome adaptation to mitochondrial damage. Hence, TRPML1 is a ROS sensor localized on the lysosomal membrane that orchestrates an autophagy-dependent negative-feedback programme to mitigate oxidative stress in the cell.
SOURCES – Nature Communications, University of Michigan