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Article

Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM

by
Gayoung Ryu
1,
Minjeong Ko
1,
Sooyeon Lee
1,
Se In Park
1,
Jin-Woong Choi
2,
Ju Yeon Lee
2,3,
Jin Young Kim
2,3 and
Ho Jeong Kwon
1,*
1
Chemical Genomics Leader Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
2
Digital Omics Research Center, Korea Basic Science Institute, Ochang 28119, Republic of Korea
3
Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
*
Author to whom correspondence should be addressed.
Biomolecules 2024, 14(12), 1505; https://doi.org/10.3390/biom14121505
Submission received: 6 October 2024 / Revised: 1 November 2024 / Accepted: 21 November 2024 / Published: 26 November 2024
(This article belongs to the Special Issue Biomolecules and Their Impact on Biology and Translational Applications: Celebrating the Pioneering Work of Prof. Ho Jeong Kwon)
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Abstract

An ellagitannin-derived metabolite, Urolithin A (UA), has emerged as a potential therapeutic agent for metabolic disorders due to its antioxidant, anti-inflammatory, and mitochondrial function-improving properties, but its efficacy in protecting against ER stress remains underexplored. The endoplasmic reticulum (ER) is a cellular organelle involved in protein folding, lipid synthesis, and calcium regulation. Perturbations in these functions can lead to ER stress, which contributes to the development and progression of metabolic disorders such as metabolic-associated fatty liver disease (MAFLD). In this study, we identified a novel target protein of UA and elucidated its mechanism for alleviating palmitic acid (PA)-induced ER stress. Cellular thermal shift assay (CETSA)-LC-MS/MS analysis revealed that UA binds directly to the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), an important regulator of calcium homeostasis in mitochondria-associated ER membranes (MAMs). As an agonist of SERCA, UA attenuates abnormal calcium fluctuations and ER stress in PA-treated liver cells, thereby contributing to cell survival. The lack of UA activity in SERCA knockdown cells suggests that UA regulates cellular homeostasis through its interaction with SERCA. Collectively, our results demonstrate that UA protects against PA-induced ER stress and enhances cell survival by regulating calcium homeostasis in MAMs through SERCA. This study highlights the potential of UA as a therapeutic agent for metabolic disorders associated with ER stress.
Keywords: Urolithin A; ER stress; MAM; CETSA-LC-MS/MS; SERCA; MAFLD Urolithin A; ER stress; MAM; CETSA-LC-MS/MS; SERCA; MAFLD

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MDPI and ACS Style

Ryu, G.; Ko, M.; Lee, S.; Park, S.I.; Choi, J.-W.; Lee, J.Y.; Kim, J.Y.; Kwon, H.J. Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM. Biomolecules 2024, 14, 1505. https://doi.org/10.3390/biom14121505

AMA Style

Ryu G, Ko M, Lee S, Park SI, Choi J-W, Lee JY, Kim JY, Kwon HJ. Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM. Biomolecules. 2024; 14(12):1505. https://doi.org/10.3390/biom14121505

Chicago/Turabian Style

Ryu, Gayoung, Minjeong Ko, Sooyeon Lee, Se In Park, Jin-Woong Choi, Ju Yeon Lee, Jin Young Kim, and Ho Jeong Kwon. 2024. "Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM" Biomolecules 14, no. 12: 1505. https://doi.org/10.3390/biom14121505

APA Style

Ryu, G., Ko, M., Lee, S., Park, S. I., Choi, J.-W., Lee, J. Y., Kim, J. Y., & Kwon, H. J. (2024). Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM. Biomolecules, 14(12), 1505. https://doi.org/10.3390/biom14121505

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