The Effects of Urolithin A on Mitochondria in Early Alzheimer's Disease
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Note From Dr. Pendleton
This article is my attempt at a simplified summary of a scientific paper I found interesting. I’m passionate about sharing scientific knowledge in a way that’s accessible to everyone. However, it's important to remember that many scientific studies, including this one, may not directly apply to you, let alone all people. For example, some studies are conducted on animals or involve small sample sizes, which limits the generalizability of the results. My goal is to present the information responsibly and in layman’s terms, so please keep in mind that the findings should be interpreted with care.
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This scientific summary is based on the scientific article titled Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease, by Carsten Esselun et al., which explores the potential neuroprotective properties of Urolithin A (UA), a metabolite derived from ellagitannins found in pomegranates and walnuts. The study investigates how UA influences mitochondrial function in SH-SY5Y neuroblastoma cells, particularly those modified to mimic early Alzheimer's disease (SH-SY5Y-APP695). The authors assess various mitochondrial parameters, including respiration, membrane potential, ATP production, autophagy, and reactive oxygen species (ROS) levels, alongside gene expression related to mitochondrial biogenesis and function.
Introduction to Urolithin A and Alzheimer's Disease
Urolithin A is made in our gut when we eat foods like pomegranates and walnuts. Alzheimer's disease affects the brain, causing memory loss and confusion.
Mitochondria, the powerhouses of cells, are essential for aging and brain health. This study looks at how Urolithin A helps protect mitochondria in the early stages of Alzheimer's.
What are Ellagitannins and How are They Metabolized?
Ellagitannins are found in certain fruits and nuts.
Sources: Pomegranates and walnuts.
Conversion Process: Our gut bacteria turn ellagitannins into ellagic acid, which then becomes Urolithin A.
Benefits: Urolithin A supports mitochondrial health and may protect the brain. "Urolithin A (UA) has been shown to cross the blood-brain barrier in-silico, as well as in-vitro."
Role in Cells: They produce energy and control cell life and death.
Impact of Alzheimer's: In Alzheimer's, mitochondria get damaged, leading to less energy and more cell death. "Mitochondrial dysfunction is characterized by changes of mitochondrial bioenergetics, e.g., impairment of the oxidative phosphorylation (OXPHOS) leading to lower mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) production" (Esselun et al., 2021).
Symptoms: This damage causes memory loss and confusion.
The Study: Purpose and Methods
The study explored how Urolithin A affects mitochondria in early Alzheimer's.
Cell Lines Used
Researchers used SH-SY5Y cells, a type of human neuroblastoma cell commonly used as a model for neuronal function and development. To create a model for early Alzheimer's disease, some of these cells were genetically modified to express the amyloid precursor protein (APP695), resulting in the SH-SY5Y-APP695 cell line.
This modification leads to the production of amyloid-beta peptide, which is associated with Alzheimer's pathology. The unmodified SH-SY5Y cells, referred to as SH-SY5Ymock, were used as controls.
Experiments Conducted
The researchers conducted a series of experiments to assess the impact of Urolithin A on mitochondrial function and related cellular processes:
Mitochondrial Respiration (Energy Production): They measured the oxygen consumption rate to evaluate how well mitochondria produced energy through oxidative phosphorylation (OXPHOS). "Treatment with 1 µM UA did not alter the respiration of SH-SY5Ymock cells...uncoupled CII and CIV respiration were significantly reduced by UA treatment in SH-SY5Y-APP695 cells."
Mitochondrial Membrane Potential (MMP): MMP is an indicator of mitochondrial health and function. The researchers assessed MMP using rhodamine-123 fluorescence. "Treatment with a 10-fold increased UA concentration (10 µM) significantly reduced MMP."
ATP Levels (Cell Energy): They measured adenosine triphosphate (ATP) levels to determine the energy available within the cells. "Examination of ATP levels revealed that treatment with 1 µM UA did not affect either parameter in the two cell lines...a similar trend was observed for the ATP concentration."
Autophagy (Cell Cleanup): Autophagy is the process of removing damaged components. The study used Western blotting and fluorescence assays to assess levels of autophagy markers such as LC3B-I, LC3B-II, and p62. "LC3B-I, LC3B-II, and p62 levels were unchanged."
Reactive Oxygen Species (ROS) Levels: ROS are indicators of oxidative stress within cells. The researchers measured ROS using DCFDA/H2DCFDA fluorescence. "Treatment with 1 µM UA for 24 h did not affect ROS production."
Gene Expression Related to Mitochondria: Using quantitative real-time PCR (qRT-PCR), they analyzed the expression of genes involved in mitochondrial bioenergetics, biogenesis, and autophagy. "UA treatment significantly increased expression of genes for mitochondrial biogenesis and OXPHOS."
Key Findings of the Study
The study found several vital effects of Urolithin A on mitochondria.
Mitochondrial Function
At 1 µM, Urolithin A did not change respiration or ATP levels but did at 10 µM. "Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS."
Gene Expression
Urolithin A increased the expression of genes related to mitochondrial biogenesis and function, especially in SH-SY5Y-APP695 cells.
Autophagy and ROS
Urolithin A did not significantly impact autophagy markers like LC3B-I, LC3B-II, and p62, or ROS levels.
Amyloid Beta Levels
Treatment with Urolithin A did not affect the levels of amyloid beta, a protein linked to Alzheimer's disease.
Detailed Explanation of Results
Mitochondrial Respiration and ATP Production: Urolithin A at 1 µM did not change respiration or ATP levels. At 10 µM, there was a decrease in MMP and ATP, suggesting high doses might be harmful. "When cells were treated with a 10-fold increased UA concentration (10 µM), MMP was significantly reduced and a similar trend was observed for the ATP concentration."
Mitochondrial Membrane Potential (MMP): MMP measures the health of mitochondrial membranes. Higher doses of Urolithin A reduced MMP, which could be toxic.
Autophagy Markers: Autophagy is how cells clean out damaged parts. Urolithin A did not significantly change autophagy markers like LC3B-I, LC3B-II, and p62. "LC3B-I, LC3B-II, and p62 levels were unchanged."
Gene Expression for Biogenesis: Urolithin A increased the expression of several genes related to mitochondrial biogenesis, like TFAM and NDUFV1, especially in Alzheimer's model cells. "Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695."
Implications of the Study
The study explains how Urolithin A could help treat Alzheimer's disease.
Potential Benefits: Urolithin A may help keep mitochondria healthy and support new mitochondria production. "Data suggests that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes."
Need for Further Research: More studies are needed to fully understand its effects and potential as a treatment option.
Therapeutic Potential: While Urolithin A shows promise in gene expression related to mitochondrial health, its direct impact on Alzheimer's' symptoms needs more study. "UA shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited."
Final Thoughts on Urolithin A and Mitochondrial Health in Alzheimer's
Urolithin A supports mitochondrial health by changing gene expression related to mitochondrial biogenesis. Its effects on mitochondrial function in Alzheimer's cells are complex and depend on the dose.
More research is needed to see if it can be a treatment for neurodegenerative diseases like Alzheimer's. "Data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis."
Meet the Author
Dr. James Pendleton
Dr. James Pendleton is a primary care physician specializing in a naturopathic approach to family medicine. He has nurtured a family practice in Seattle, directed a VIP medical center in Abu Dhabi, published several books and scientific articles, and designed innovative nutritional supplements for manufacturers worldwide.
REFERENCES
Anderson, A. J., Jackson, T. D., Stroud, D. A., & Stojanovski, D. (2019). Mitochondria-hubs for regulating cellular biochemistry: emerging concepts and networks. Open biology, 9(8), 190126. https://doi.org/10.1098/rsob.190126
Faitg, J., D’Amico, D., Rinsch, C. et al. Mitophagy Activation by Urolithin A to Target Muscle Aging. Calcif Tissue Int114 , 53–59 (2024). https://doi.org/10.1007/s00223-023-01145-5
Zhao, H., Song, G., Zhu, H., Qian, H., Pan, X., Song, X., Xie, Y., & Liu, C. (2023). Pharmacological Effects of Urolithin A and Its Role in Muscle Health and Performance: Current Knowledge and Prospects. Nutrients, 15(20), 4441. https://doi.org/10.3390/nu15204441
Esselun, Carsten, Ellen Theyssen, and Gunter P. Eckert. 2021. "Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease" International Journal of Molecular Sciences 22, no. 15: 8333. https://doi.org/10.3390/ijms22158333