Diabetes, cancer, and Parkinson’s disease are becoming more prevalent* globally. The worldwide diabetes prevalence in 2019 was estimated to be 9.3% (463 million people), rising to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. (1) According to International Agency for Research on Cancer (IARC), there were an estimated 18.1 million (95% UI: 17.5-18.7 million) new cases of cancer (17 million excluding non-melanoma skin cancer) and 9.6 million (95% UI: 9.3-9.8 million) deaths from cancer (9.5 million excluding non-melanoma skin cancer) worldwide in 2018. (2) And Parkinson’s disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented. (3)
More and more studies are being done to understand the course of these diseases and to improve treatments and interventions. One of them was made by researchers of the Salk Institute for Biological Studies, who discovered a direct link between a master sensor of cell stress and Parkin, the gene product of the E3 ubiquitin ligase* gene PARK2 in Parkinson’s disease. That pathway is related to type 2 diabetes and cancer. This discovery is significant to future researches for treating all three diseases.
Professor Reuben Shaw, director of the NCI-designated Salk Cancer Center, said “Decoding this major step in the way cells dispose of defective mitochondria has implications for several diseases.”
Studies linking Parkinson’s disease(PD) to defects in the electron transport chain suggest that damaged mitochondria, the power stations that generate energy for the cell, may play a central role in PD pathology (4). Studies of two recessive Parkinson’s disease genes, PINK1, and parkin (PARK2) have provided direct evidence for the contribution of damaged mitochondria in PD pathology. (5) (6) Parking and PINK1 are involved in a common pathway regulating mitochondrial quality control and promoting the selective autophagy* of depolarized mitochondria (mitophagy)*. (6) (7)
Furthermore, the adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK) pathway, in addition to PINK1-Parkin, is another cellular stress-sensing pathway that plays a role in mitochondrial homeostasis*. (8)
The researchers looked at about 50 different proteins and estimated that about 10% of them would suit. When parkin came in first, they were taken aback. These findings reveal a surprising and fast new phase in Parkin biochemical activation following a mitochondrial disruption. Biochemical pathways are typically complex, involving up to 50 players, each of whom activates the other. They noticed that a process as significant as mitophagy is initiated by only three participants: AMPK, then ULK1, then Parkin.
They used mass spectrometry* to confirm the findings, pinpointing precisely where ULK1 was binding a phosphate group to Parkin. They found that it landed in a previously inaccessible region that had recently been discovered to be crucial for Parkin activation by other researchers.
Shaw’s research is only getting started on understanding this critical first step of Parkin activation, which he claims acts as a “heads-up” alert from AMPK down the chain of command from ULK1 to Parkin to go check out the mitochondria after the first wave of incoming damage and, if possible, trigger the death of those mitochondria that are too weak to recover function.
The outcomes have far-reaching implications. AMPK, a central sensor of the cell’s metabolism, is activated by a tumor suppressor protein called LKB1 that is involved 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 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.” Additionally, “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.”
Summing up, the investigation identified a novel site of parkin regulation directly downstream of AMPK/ULK1 pathway activation and forces a revision of dogma regarding when and where Parkin function may be important. (8) The ability of ULK1 to phosphorylate Ser108 in the Parkin ACT element following even mild mitochondrial stresses—including metformin—begets questions of whether this event serves as an “early alert signal” of mitochondrial damage and may play a surveillance/proteostatic role in some biological contexts.
The consistent relationship between AMPK and ULK1 and Parkin opens up dozens of new research possibilities, including Parkinson’s disease, cancer, and diabetes.
Prevalence: This is the proportion of a population who have a specific characteristic in a given period. May be reported as a percentage (5%, or 5 people out of 100), or as the number of cases per 10,000 or 100,000 people. (9)
Ligase:(biochemistry) An enzyme that catalyzes the binding of two molecules. (10)
Autophagy: A programmed cell death characterized by biochemical events leading to self-digestion through the destructive action of enzymes produced by the cell itself, often as a defensive or self-preservation response. (11)
Mitophagy: is the mechanism by which impaired or superfluous mitochondria are engulfed in autophagosomes to be then degraded into lysosomes. (12)
Homeostasis: from the Greek words for “same” and “steady,” refers to any process that living things use to actively maintain fairly stable conditions necessary for survival. (13)
Metformine: An oral medicine used to treat type 2 diabetes. Metformin lowers blood glucose by reducing the amount of glucose produced by the liver and helping the body respond better to the insulin made in the pancreas. (14)
Spectrometry: it is a method used by scientists to measure and compare the mass and the electrical charge of ions. (15)
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- Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D. M., Piñeros, M., Znaor, A., & Bray, F. (2019). Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International journal of cancer, 144(8), 1941–1953. https://doi.org/10.1002/ijc.31937
- Cabreira, V., & Massano, J. (2019). Doença de Parkinson: Revisão Clínica e Atualização [Parkinson’s Disease: Clinical Review and Update]. Acta medica portuguesa, 32(10), 661–670. https://doi.org/10.20344/amp.11978
- Moon, H. E., & Paek, S. H. (2015). Mitochondrial Dysfunction in Parkinson’s Disease. Experimental neurobiology, 24(2), 103–116. https://doi.org/10.5607/en.2015.24.2.103
- Hereditary early-onset Parkinson’s disease 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):1158-60.
- 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 Apr 9; 392(6676):605-8.
- 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. AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Science Advances, 2021; 7 (15): eabg4544 DOI: https://advances.sciencemag.org/content/7/15/eabg4544.
- NIMH » What is Prevalence?. Nimh.nih.gov. (2021). Retrieved 11 April 2021, from https://www.nimh.nih.gov/health/statistics/what-is-prevalence.shtml.
- Ligase. Biology online. (2021). Retrieved 11 April 2021, from https://www.biologyonline.com/dictionary/ligase.
- Autophagy. Biology online. (2021). Retrieved 11 April 2021, from https://www.biologyonline.com/dictionary/Autophagy.
- Mitophagy – an overview | ScienceDirect Topics. Sciencedirect.com. (2021). Retrieved 12 April 2021, from https://www.sciencedirect.com/topics/immunology-and-microbiology/mitophagy.
- Gustafsson, Å. B., & Dorn, G. W., 2nd (2019). Evolving and Expanding the Roles 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, Medicines, & Other Diabetes Treatments | NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 12 April 2021, from https://www.niddk.nih.gov/health-information/diabetes/overview/insulin-medicines-treatments.
- Urban P. L. (2016). Quantitative mass spectrometry: an overview. Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, 374(2079), 20150382. https://doi.org/10.1098/rsta.2015.0382