Enzyme with central role in cancer and type 2 diabetes also activates
“clean-up” protein in Parkinson’s.
When cells are stressed, chemical alarms go off, setting in motion a flurry
of activity that protects the cell’s most important players. During the
rush, a protein called Parkin hurries to protect the mitochondria, the power
stations that generate energy for the cell. Now Salk researchers have
discovered a direct link between a master sensor of cell stress and Parkin
itself. The same pathway is also tied to type 2 diabetes and cancer, which
could open a new avenue for treating all three diseases.
“Our findings represent the earliest step in Parkin’s alarm response that
anyone’s ever found by a long shot. All the other known biochemical events
happen at one hour; we’ve now found something that happens within five
minutes,” says Professor Reuben Shaw, director of the NCI-designated Salk
Cancer Center and senior author of the new work, detailed in Science
Advances on April 7, 2021. “Decoding this major step in the way cells
dispose of defective mitochondria has implications for a number of
diseases.”
Parkin’s job is to clear away mitochondria that have been damaged by
cellular stress so that new ones can take their place, a process called
mitophagy. However, Parkin is mutated in familial Parkinson’s disease,
making the protein unable to clear away damaged mitochondria. While
scientists have known for some time that Parkin somehow senses mitochondrial
stress and initiates the process of mitophagy, no one understood exactly how
Parkin was first sensing problems with the mitochondria—Parkin somehow knew
to migrate to the mitochondria after mitochondrial damage, but there was no
known signal to Parkin until after it arrived there.
Shaw’s lab, which is well known for their work in the fields of metabolism
and cancer, spent years intensely researching how the cell regulates a more
general process of cellular cleaning and recycling called autophagy. About
ten years ago, they discovered that an enzyme called AMPK, which is highly
sensitive to cellular stress of many kinds, including mitochondrial damage,
controls autophagy by activating an enzyme called ULK1.
Following that discovery, Shaw and graduate student Portia Lombardo began
searching for autophagy-related proteins directly activated by ULK1. They
screened about 50 different proteins, expecting about 10 percent to fit.
They were shocked when Parkin topped the list. Biochemical pathways are
usually very convoluted, involving up to 50 participants, each activating
the next. Finding that a process as important as mitophagy is initiated by
only three participants—first AMPK, then ULK1, then Parkin—was so surprising
that Shaw could scarcely believe it.
To confirm the findings were correct, the team used mass spectrometry to
reveal precisely where ULK1 was attaching a phosphate group to Parkin. They
found that it landed in a new region other researchers had recently found to
be critical for Parkin activation but hadn’t known why. A postdoctoral
fellow in Shaw’s lab, Chien-Min Hung, then did precise biochemical studies
to prove each aspect of the timeline and delineated which proteins were
doing what, and where. Shaw’s research now begins to explain this key first
step in Parkin activation, which Shaw hypothesizes may serve as a “heads-up”
signal from AMPK down the chain of command through ULK1 to Parkin to go
check out the mitochondria after a first wave of incoming damage, and, if
necessary, trigger destruction of those mitochondria that are too gravely
damaged to regain function.
The findings have wide-ranging implications. AMPK, the central sensor of the
cell’s metabolism, is itself activated by a tumor suppressor protein called
LKB1 that is involved in a number of cancers, as established by Shaw in
prior work, and it is activated by a type 2 diabetes drug called metformin.
Meanwhile, numerous studies show that diabetes patients taking metformin
exhibit lower risks of both cancer and aging comorbidities. Indeed,
metformin is currently being pursued as one of the first ever “anti-aging”
therapeutics in clinical trials.
“The big takeaway for me is that metabolism and changes in the health of
your mitochondria are critical in cancer, they’re critical in diabetes, and
they’re critical in neurodegenerative diseases,” says Shaw, who holds the
William R. Brody Chair. “Our finding says that a diabetes drug that
activates AMPK, which we previously showed can suppress cancer, may also
help restore function in patients with neurodegenerative disease. That’s
because the general mechanisms that underpin the health of the cells in our
bodies are way more integrated than anyone could have ever imagined.”
Reference:
“AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early
step in mitophagy” by Chien-Min Hung, Portia S. Lombardo, Nazma Malik, Sonja
N. Brun, Kristina Hellberg, Jeanine L. Van Nostrand, Daniel Garcia, Joshua
Baumgart, Ken Diffenderfer, John M. Asara and Reuben J. Shaw, 7 April 2021,
Science Advances. DOI:
10.1126/sciadv.abg4544