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Introduction: Enzymes that play a major role in cancer and type 2 diabetes can also activate the "clear" protein in Parkinson's disease.
When the cell is under pressure, a chemical alarm will sound, which initiates a series of activities to protect the core part of the cell.
At its peak, a protein called Parkin is eager to protect mitochondria, which are power plants that generate energy for cells.
Recently, Salk researchers discovered a direct connection between the main sensors of cellular stress and Parkin itself.
The same approach is also related to type 2 diabetes and cancer, which may open up a new way to treat these three diseases.
Professor Reuben Shaw, the director of the Salk Cancer Center designated by NCI and the senior author of the new study, said: "Our discovery represents the earliest step in Parkin's alert response.
All other known biochemical events occurred within an hour.
We It has now been discovered that some activity has occurred within five minutes.
This important step in the way cells dispose of defective mitochondria has an impact on many diseases.
” The paper was published in the Science Advances on April 7, 2021 .
) Has a detailed introduction.
Parkin's job is to remove mitochondria that have been damaged by cellular stress so that new mitochondria can take their place.
This process is called mitosis.
However, Parkin is mutated in familial Parkinson's disease, making the protein unable to clear the damaged mitochondria.
Although scientists already know that Parkin somehow senses mitochondrial pressure and initiates the process of mitosis, no one knows exactly how Parkin perceives mitochondrial problems in the first place.
Parkin somehow knew that the mitochondria migrated to mitochondria after damage, but before it reached the mitochondria, there was no known signal to Parkin.
Shaw's laboratory is well-known for its work in the areas of metabolism and cancer, and it has spent many years studying in depth how cells regulate the cell's more general cell cleaning and recycling process, known as autophagy.
About ten years ago, they discovered that an enzyme called AMPK controls autophagy by activating an enzyme called ULK1, which is highly sensitive to a variety of cellular stresses including mitochondrial damage.
After the discovery, Shaw and graduate student Portia Lombardo began searching for autophagy-related proteins that are directly activated by ULK1.
They screened about 50 different proteins and estimated that about 10% would be suitable.
When Parkin topped the list, they were shocked.
Biochemical pathways are usually very complex, involving up to 50 participants, each of which activates the next.
It is surprising that only three participants (AMPK, ULK1, Parkin) initiated a process as important as mitochondrial phagocytosis, so that Shaw hardly believed it.
In order to confirm the correctness of the research results, the research team used mass spectrometry to accurately reveal the position where ULK1 attaches the phosphate group to Parkin.
They discovered that it landed in a new area, and other researchers recently discovered that this area is critical to Parkin's activation, but they have not known why.
Chien-Min Hung, a postdoctoral researcher in Shaw's lab, then did precise biochemical research to prove every aspect of the timeline and outline which proteins are doing what and where.
Shaw’s research is now beginning to explain the critical first step of Parkin activation.
Shaw speculates that this may be the "warning" signal sent by AMPK to Parkin through ULK1, allowing Parkin to check mitochondria after the first wave of damage, and if necessary It triggers the destruction of mitochondria that are severely damaged and cannot restore function. In this study, the researchers found that Parkin, the core ubiquitin ligase in mitosis, and the product of the PARK2 gene mutated in familial Parkinson's disease, are the substrates of ULK1.
A recent study found a 9-residue ("ACT") domain that is important for Parkin activation.
This study demonstrated that AMPK-dependent ULK1 rapidly phosphorylates the conserved serine 108 in the ACT domain under mitochondrial stress.
The phosphorylation of Parkin Ser108 occurs within 5 minutes of mitochondrial damage, which is different from the activation of PINK1 and TBK1, which is observed after 30 to 60 minutes.
Mutations in the phosphorylation site of ULK1 in Parkin, inherited AMPK or ULK1 depletion, or drug-induced ULK1 inhibition can all lead to delayed Parkin activation and defects in Parkin function and detection of downstream mitotic events.
These findings reveal an unexpected first step in the mitotic cascade.
At time 0, Parkin protein (green signal) and mitochondria (red signal) are located in different parts of the cell (left image), but after 60 minutes they co-localize with mitochondria (right image).
The maximum Parkin activity depends on ULK1 Parkin These findings of phosphorylation have broad implications.
AMPK is the core sensor of cell metabolism.
It itself is activated by a tumor suppressor protein called LKB1, and LKB1 is related to a variety of cancers.
Shaw has determined in previous work that it will also be activated by a kind of metformin.
Activation of type 2 diabetes drugs.
At the same time, a large number of studies have shown that diabetes patients taking metformin have a lower risk of cancer and aging complications.
In fact, metformin is currently being used in clinical trials as one of the earliest "anti-aging" therapies.
Shaw, chairman of William R.
Brody, said: "For me, the biggest gain is that changes in metabolism and mitochondrial health are critical to cancer, diabetes, and neurodegenerative diseases. Our findings indicate that our previously shown diabetes drugs that activate AMPK can inhibit cancer and may also help restore function in patients with neurodegenerative diseases.
This is because the general mechanisms that support cell health in our bodies are more integrated than anyone can imagine.
"Original source: AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy.
Science Advances: 7 (15).
DOI: 10.
1126/sciadv.
abg4544
When the cell is under pressure, a chemical alarm will sound, which initiates a series of activities to protect the core part of the cell.
At its peak, a protein called Parkin is eager to protect mitochondria, which are power plants that generate energy for cells.
Recently, Salk researchers discovered a direct connection between the main sensors of cellular stress and Parkin itself.
The same approach is also related to type 2 diabetes and cancer, which may open up a new way to treat these three diseases.
Professor Reuben Shaw, the director of the Salk Cancer Center designated by NCI and the senior author of the new study, said: "Our discovery represents the earliest step in Parkin's alert response.
All other known biochemical events occurred within an hour.
We It has now been discovered that some activity has occurred within five minutes.
This important step in the way cells dispose of defective mitochondria has an impact on many diseases.
” The paper was published in the Science Advances on April 7, 2021 .
) Has a detailed introduction.
Parkin's job is to remove mitochondria that have been damaged by cellular stress so that new mitochondria can take their place.
This process is called mitosis.
However, Parkin is mutated in familial Parkinson's disease, making the protein unable to clear the damaged mitochondria.
Although scientists already know that Parkin somehow senses mitochondrial pressure and initiates the process of mitosis, no one knows exactly how Parkin perceives mitochondrial problems in the first place.
Parkin somehow knew that the mitochondria migrated to mitochondria after damage, but before it reached the mitochondria, there was no known signal to Parkin.
Shaw's laboratory is well-known for its work in the areas of metabolism and cancer, and it has spent many years studying in depth how cells regulate the cell's more general cell cleaning and recycling process, known as autophagy.
About ten years ago, they discovered that an enzyme called AMPK controls autophagy by activating an enzyme called ULK1, which is highly sensitive to a variety of cellular stresses including mitochondrial damage.
After the discovery, Shaw and graduate student Portia Lombardo began searching for autophagy-related proteins that are directly activated by ULK1.
They screened about 50 different proteins and estimated that about 10% would be suitable.
When Parkin topped the list, they were shocked.
Biochemical pathways are usually very complex, involving up to 50 participants, each of which activates the next.
It is surprising that only three participants (AMPK, ULK1, Parkin) initiated a process as important as mitochondrial phagocytosis, so that Shaw hardly believed it.
In order to confirm the correctness of the research results, the research team used mass spectrometry to accurately reveal the position where ULK1 attaches the phosphate group to Parkin.
They discovered that it landed in a new area, and other researchers recently discovered that this area is critical to Parkin's activation, but they have not known why.
Chien-Min Hung, a postdoctoral researcher in Shaw's lab, then did precise biochemical research to prove every aspect of the timeline and outline which proteins are doing what and where.
Shaw’s research is now beginning to explain the critical first step of Parkin activation.
Shaw speculates that this may be the "warning" signal sent by AMPK to Parkin through ULK1, allowing Parkin to check mitochondria after the first wave of damage, and if necessary It triggers the destruction of mitochondria that are severely damaged and cannot restore function. In this study, the researchers found that Parkin, the core ubiquitin ligase in mitosis, and the product of the PARK2 gene mutated in familial Parkinson's disease, are the substrates of ULK1.
A recent study found a 9-residue ("ACT") domain that is important for Parkin activation.
This study demonstrated that AMPK-dependent ULK1 rapidly phosphorylates the conserved serine 108 in the ACT domain under mitochondrial stress.
The phosphorylation of Parkin Ser108 occurs within 5 minutes of mitochondrial damage, which is different from the activation of PINK1 and TBK1, which is observed after 30 to 60 minutes.
Mutations in the phosphorylation site of ULK1 in Parkin, inherited AMPK or ULK1 depletion, or drug-induced ULK1 inhibition can all lead to delayed Parkin activation and defects in Parkin function and detection of downstream mitotic events.
These findings reveal an unexpected first step in the mitotic cascade.
At time 0, Parkin protein (green signal) and mitochondria (red signal) are located in different parts of the cell (left image), but after 60 minutes they co-localize with mitochondria (right image).
The maximum Parkin activity depends on ULK1 Parkin These findings of phosphorylation have broad implications.
AMPK is the core sensor of cell metabolism.
It itself is activated by a tumor suppressor protein called LKB1, and LKB1 is related to a variety of cancers.
Shaw has determined in previous work that it will also be activated by a kind of metformin.
Activation of type 2 diabetes drugs.
At the same time, a large number of studies have shown that diabetes patients taking metformin have a lower risk of cancer and aging complications.
In fact, metformin is currently being used in clinical trials as one of the earliest "anti-aging" therapies.
Shaw, chairman of William R.
Brody, said: "For me, the biggest gain is that changes in metabolism and mitochondrial health are critical to cancer, diabetes, and neurodegenerative diseases. Our findings indicate that our previously shown diabetes drugs that activate AMPK can inhibit cancer and may also help restore function in patients with neurodegenerative diseases.
This is because the general mechanisms that support cell health in our bodies are more integrated than anyone can imagine.
"Original source: AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy.
Science Advances: 7 (15).
DOI: 10.
1126/sciadv.
abg4544
