Scientists have discovered a direct link between a major sensor of cell stress and a protein that protects the cells' power plants. The new findings could give a new direction to the search for therapies for all three diseases.
When cells are exposed to stress, chemical alarms sound off and a storm of activity is set in motion to protect the cell's key players. Among other things, a protein called parkin, which is considered essential for cell health and energy production, rushes in during this flurry.
Cellular stress can damage our mitochondria. Such damaged or dysfunctional mitochondria would accumulate in cells over time - were it not for a clean-up process called mitophagy. It removes defective mitochondria and makes room for new ones. Parkin is an essential protein for this process. A disturbed function of the mitochondria has already been described in various neurodegenerative diseases. In particular, when parkin does not function properly, cancer, Parkinson's disease and type 2 diabetes can occur.
But until recently, how parkin so quickly recognises mitochondrial stress and initiates mitophagy remained a mystery. The signals for parkin to get to work seemed to occur after it had already migrated to the defective mitochondria and iit was in action.
This has now changed, as researchers from the prestigious Salk Institute recently published in the journal Science Advances the latest findings on the start of the Parkin signalling pathway.1-3 Their findings represent by far the earliest step in the Parkin reaction chain that anyone has ever found. "All other known biochemical events happen within 1 hour; we have now found something that happens within 5 minutes," the authors say.
About a decade ago, this team looked at a more overarching clean-up process, autophagy, and discovered that an enzyme called AMPK, which is very sensitive to cellular stress of many kinds (including mitochondrial damage), controls autophagy by activating an enzyme called ULK1. The next step was to look for proteins that are activated by ULK1. The scientists expected numerous hits, because biochemical pathways are often very complex, with up to 50 contributors involved, each activating the next.
To their great surprise, one protein topped the list: Parkin. The finding that a process as important as mitophagy is initiated by only three players - first AMPK, then ULK1, then Parkin - was so surprising that the authors could hardly believe it.
They validated their discovery in subsequent studies, including mass spectrometry that reveals exactly where ULK1 attaches a phosphate group to Parkin. They also conducted detailed biochemical studies to prove every aspect of the timeline and show which proteins do what.
It is this chain, from AMPK to ULK1 to Parkin, that is responsible for the speed with which Parkin can respond to cellular stress. So a "heads-up" signal from AMPK runs down the chain of command via ULK1 and reaches Parkin so that it checks the mitochondria for new incoming damage and, if necessary, triggers the destruction of those mitochondria that are too badly damaged to regain their function.
"Deciphering this important step in how cells sort out defective mitochondria has implications for a range of diseases." The finding that AMPK and Parkin are closely linked could benefit the development of new therapies. AMPK, the central sensor of cellular metabolism, is in turn activated by a tumour suppressor protein called LKB1, which has been implicated in a number of cancers. Accordingly, an AMPK-activating diabetes drug, metformin, which the same research group has previously shown can suppress cancer, could also help restore function in patients with neurodegenerative diseases.
Prof Reuben Shaw, director of the Salk Cancer Center in La Jolla, California, and main study author summarises: "The big finding is that metabolism and changes in mitochondrial health are critical for cancer, they're critical for diabetes, and they're critical for neurodegenerative disease."
References:
1. Hung, C.-M. et al. AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Science Advances 7, eabg4544 (2021).
2. Parkinson's, cancer, and diabetes may all share one key factor. https://www.medicalnewstoday.com/articles/key-pathway-in-parkinsons-may-help-treatments-for-cancer-diabetes (2021).
3. Parkinson's, cancer, type 2 diabetes share a key element that drives disease: Enzyme with central role in cancer and type 2 diabetes also activates. ScienceDaily https://www.sciencedaily.com/releases/2021/04/210408112344.htm.