We all use the word stress very frequently. And it is normal considering that our life is particularly hectic. As it is logical to think, cells are also affected by continuous stress. In this case, in fact, several chemical alarms are activated, triggering a dangerous series of chain reactions which are intended to protect some cellular components but which, in the long run, could give rise to various diseases, including Parkinson’s, diabetes and cancer. Damage caused by stress
When the cells of the human body are stressed, mechanisms are activated to protect the most important cellular elements. On this occasion, a protein called Parkin runs to protect the mitochondria, the power plants that generate energy for each cell. And it is Parkin that seems to play a fundamental role in the emergence of numerous diseases, including diabetes, cancer and Parkinson’s. “Our findings represent the first step in responding to Parkin’s alarm. All other known biochemical events occur within one hour; now we have found something that happens within five minutes. Decoding this important step in how cells dispose of defective mitochondria has implications for a number of diseases, ‘explains Professor Reuben Shaw.Parkin and cellular stress
As mentioned, the Parkin protein has the precise task of eliminating mitochondria that have been damaged by cellular stress so that new ones can take their place. This process is called mitophagy. In Parkinson’s disease patients, however, it can be seen that Parkin has mutated in such a way that it cannot eliminate damaged mitochondria. Scientists have long known that Parkin perceives mitochondrial stress by initiating the process of mitophagy, but no one had understood how the protein perceives problems with mitochondria. Shaw’s lab, known for its work in the fields of metabolism and cancer, has conducted years and years of research to understand how cell cleansing or autophagy works. Ten years ago, he discovered that an enzyme called AMPK, was highly sensitive to cellular stress of many types, including mitochondrial damage, controlling autophagy by means of an enzyme called ULK1. Thanks to this discovery, Professor Shaw, along with a student named Portia Lombardo, began looking for all the proteins related to autophagy and ULK1. The results showed that Parkin tops the list. The biochemical pathways are usually very convoluted, involving up to 50 elements, each of which activates the next. Finding that such an important process as mitophagy started with only three elements – first AMPK, then ULK1, then Parkin – was so surprising that Shaw could hardly believe it. Thanks to this discovery, Professor Shaw, along with a student named Portia Lombardo, began looking for all the proteins related to autophagy and ULK1. The results showed that Parkin tops the list. The biochemical pathways are usually very convoluted, involving up to 50 elements, each of which activates the next. Finding that such an important process as mitophagy started with only three elements – first AMPK, then ULK1, then Parkin – was so surprising that Shaw could hardly believe it. Thanks to this discovery, Professor Shaw, along with a student named Portia Lombardo, began looking for all the proteins related to autophagy and ULK1. The results showed that Parkin tops the list. The biochemical pathways are usually very convoluted, involving up to 50 elements, each of which activates the next. Finding that such an important process as mitophagy started with only three elements – first AMPK, then ULK1, then Parkin – was so surprising that Shaw could hardly believe it.Cellular stress, diabetes, cancer and Parkinson’s
AMPK, the central sensor of cellular metabolism, is activated by a tumor suppressor protein called LKB1, which is involved in a number of cancers. But it is also activated by a type 2 diabetes drug called metformin. Meanwhile, numerous studies show that diabetic patients taking metformin have lower risks of both cancer and comorbid aging. In fact, metformin is currently being pursued as one of the first ever “anti-aging” therapies in clinical trials. “Most important to me is that metabolism and changes in the health of your mitochondria are critical for cancer, are critical for diabetes, and are critical for neurodegenerative diseases. Our discovery states that a diabetes drug that activates AMPK, which we have previously shown can suppress cancer, it can also help restore function in patients with neurodegenerative diseases. This is because the general mechanisms that underlie the health of the cells in our body are much more integrated than anyone could ever have imagined, ”concludes Shaw.Fonti scientifiche
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 “clean-up” protein in Parkinson’s – SALK INSTITUTE
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, Reuben J. Shaw. AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Science Advances, 2021; 7 (15): eabg4544 DOI: 10.1126/sciadv.abg4544
