Diabetes, cancer and Parkinson’s are becoming more common worldwide *. The global diabetes prevalence in 2019 was estimated at 9.3% (463 million people) and increased to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. (1) According to the International Agency for Research on Cancer (IARC), there were an estimated 18.1 million (95% UI: 17.5-18.7 million) new cancer cases (17 million without skin cancer without melanoma) and 9.6 million (95% UI: 17.5-18.7 million) % UI: 9.3-9.8 million) deaths from cancer (9.5 million (excluding skin cancer, excluding melanoma) in 2018. (2) Parkinson’s disease is the second most common neurodegenerative disease, and a significant increase in its prevalence in the last three decades has been documented. (3)
Mitochondria
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More and more studies are being conducted to understand the course of these diseases and to improve treatments and interventions. One of these was made by researchers at the Salk Institute for Biological Studies, who discovered a direct link between a master cell stress sensor and parkin, the gene product of the E3 ubiquitin ligase * gene PARK2 in Parkinson’s disease. This path is related to type 2 diabetes and cancer. This discovery is important for future research into the treatment of all three diseases.
Professor Reuben Shaw, director of the NCI-designated Salk Cancer Center, said, “Unraveling this important step in the way cells dispose of defective mitochondria has implications for a number of diseases.”
Studies linking Parkinson’s disease (PD) to defects in the electron transport chain suggest that damaged mitochondria, the powerhouses that generate energy for the cell, may play a central role in PD pathology (4). Studies with two recessive Parkinson’s genes, PINK1 and Parkin (PARK2), have provided direct evidence of the contribution of damaged mitochondria to PD pathology. (5) (6) Parken and PINK1 share a common pathway that regulates mitochondrial quality control and promotes selective autophagy * depolarized mitochondria (mitophagy) *. (6) (7)
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In addition, the adenosine 5′-monophosphate (AMP) -activated protein kinase (AMPK) pathway, alongside PINK1-Parkin, is another cellular stress sensor pathway that plays a role in mitochondrial homeostasis *. (8th)
The researchers examined about 50 different proteins and estimated that about 10% of them would fit. When Parkin first walked in, they were surprised. These results show a surprising and rapid new phase in the biochemical activation of Parkin after mitochondrial disorder. Biochemical pathways are typically complex and involve up to 50 players, each activating the other. They found that a process as important as mitophagy is only initiated by three participants: AMPK, then ULK1, then Parkin.
They used mass spectrometry * to confirm the results and pinpoint exactly where ULK1 attaches a phosphate group to Parkin. They found it landed in a previously inaccessible region recently discovered by other researchers to be critical in park inactivation.
Shaw’s research only begins by understanding this critical first step in park inactivation, which he believes will act as a “heads-up” alarm from AMPK down the chain of command from ULK1 to Parkin to examine the mitochondria after the first wave of incoming damage and damage , if possible, trigger the death of those mitochondria that are too weak to restore function.
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The results have far-reaching implications. AMPK, a central sensor in cell metabolism, is activated by a tumor suppressor protein called LKB1, which is implicated in many cancers, and it is also activated by metformin *, a type 2 diabetes drug, according to Shaw’s previous study.
Shaw says, “The big plus for me is that metabolism and changes in the health of your mitochondria are critical in cancer, diabetes, and neurodegenerative diseases.” In addition, it says: “Our finding is that a diabetes drug that activates AMPK, which we previously showed can suppress cancer, can also help restore function in patients with neurodegenerative diseases. This is because the general mechanisms that support the health of the cells in our body are much more integrated than anyone could ever have imagined. “
In summary, the investigation identified a novel site of park inregulation directly downstream of the activation of the AMPK / ULK1 signaling pathway and forced a revision of the dogma of when and where parkin function could be important. (8) The ability of ULK1 to phosphorylate Ser108 in the Parkin ACT element after even mild mitochondrial exposure, including metformin, raises questions as to whether this event serves as an “early warning signal” for mitochondrial damage and possibly has a monitoring / proteostatic role some biological relationships.
The consistent relationship between AMPK and ULK1 and Parkin opens up dozens of new research opportunities, including Parkinson’s, cancer, and diabetes.
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Definitions
Prevalence: This is the proportion of a population that shows a certain characteristic in a certain period of time. Can be expressed as a percentage (5% or 5 in 100 people) or as the number of cases per 10,000 or 100,000 people. (9)
Ligase: (biochemistry) An enzyme that catalyzes the bond between two molecules. (10)
Autophagy: A programmed cell death characterized by biochemical events that lead to self-digestion through the destructive action of enzymes produced by the cell itself, often as a defensive or self-sustaining response. (11)
Mitophagy: is the mechanism by which impaired or redundant mitochondria become trapped in autophagosomes and then broken down into lysosomes. (12)
Homeostasis: From the Greek words for “equal” and “steady” refers to any process that living things use to actively maintain fairly stable conditions necessary for survival. (13)
Metformin: an oral medicine used to treat type 2 diabetes. Metformin lowers blood sugar by reducing the amount of glucose made by the liver and by helping the body respond better to the insulin made by the pancreas. (14)
Spectrometry: This method is used by scientists to measure and compare the mass and electrical charge of ions. (fifteen)
References
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- J. Ferlay, M. Colombet, I. Soerjomataram, C. Mathers, DM Parkin, M. Piñeros, A. Znaor & F. Bray (2019). 2018 World Cancer Incidence and Mortality Estimate: GLOBOCAN Sources and Methods. International Journal of Cancer, 144 (8), 1941-1953. https://doi.org/10.1002/ijc.31937
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- Hereditary Parkinson’s disease with early onset caused by mutations in PINK1. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K., Gispert S., Ali Z., Del Turco D., Bentivoglio AR, Healy DG, Albanese A., Nussbaum R., González-Maldonado R. , Deller T., Salvi S., Cortelli P., Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B., Auburger G., Wood NW Science. 2004 May 21; 304 (5674): 1158-1. 60.
- Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y., Shimizu N. Nature. 1998, April 9; 392 (6676): 605-8.8.
- Liu, J., Liu, W., Li, R. & Yang, H. (2019). Mitophagy in Parkinson’s Disease: From Pathogenesis to Treatment. Cells, 8 (7), 712. https://doi.org/10.3390/cells8070712.
- 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. The AMPK / ULK1-mediated phosphorylation of the Parkin ACT domain mediates an early step in mitophagy. Scientific Advances, 2021; 7 (15): eabg4544 DOI: https://advances.sciencemag.org/content/7/15/eabg4544.
- NIMH »What is Prevalence ?. Nimh.nih.gov. (2021). Retrieved April 11, 2021 from https://www.nimh.nih.gov/health/statistics/what-is-prevalence.shtml.
- Ligase. Biology online. (2021). Retrieved April 11, 2021 from https://www.biologyonline.com/dictionary/ligase.
- Autophagy. Biology online. (2021). Retrieved April 11, 2021 from https://www.biologyonline.com/dictionary/Autophagy.
- Mitophagy – An Overview of ScienceDirect Topics. Sciencedirect.com. (2021). Retrieved April 12, 2021 from https://www.sciencedirect.com/topics/immunology-and-microbiology/mitophagy.
- Gustafsson, Å. B. & Dorn, GW, 2. (2019). Development and expansion of the role of mitophagy as a homeostatic and pathogenic process. Physiological Reviews, 99 (1), 853-892. https://doi.org/10.1152/physrev.00005.2018
- Information, H., Overview, D., Insulin &., Insulin &. & Health, N. (2021). Insulin, Medications, and Other Diabetes Treatments NIDDK. National Institute for Diabetes and Digestive and Kidney Diseases. Retrieved April 12, 2021 from https://www.niddk.nih.gov/health-information/diabetes/overview/insulin-medicines-treatments.
- Urban PL (2016). Quantitative mass spectrometry: an overview. Philosophical Transactions. Series A, Mathematics, Physics and Engineering, 374 (2079), 20150382. https://doi.org/10.1098/rsta.2015.0382
