Lighting up arginine metabolism reveals its functional diversity in physiology and pathology

Rui Li; Yan Li; Kun Jiang; Lijuan Zhang; Ting Li; Aihua Zhao; Zhuo Zhang; Yale Xia; Kun Ge; Yaqiong Chen; Chengnuo Wang; Weitao Tang; Shuning Liu; Xiaoxi Lin; Yuqin Song; Jie Mei; Chun Xiao; Aoxue Wang; Yejun Zou; Xie Li; Xianjun Chen; Zhenyu Ju; Wei Jia; Joseph Loscalzo; Yu Sun; Wei Fang; Yi Yang; Yuzheng Zhao

doi:10.1016/j.cmet.2024.09.011

Lighting up arginine metabolism reveals its functional diversity in physiology and pathology

Cell Metab. 2024 Oct 14:S1550-4131(24)00375-9. doi: 10.1016/j.cmet.2024.09.011. Online ahead of print.

Authors

Rui Li¹, Yan Li², Kun Jiang¹, Lijuan Zhang³, Ting Li¹, Aihua Zhao⁴, Zhuo Zhang¹, Yale Xia³, Kun Ge⁴, Yaqiong Chen³, Chengnuo Wang³, Weitao Tang³, Shuning Liu³, Xiaoxi Lin⁵, Yuqin Song⁶, Jie Mei³, Chun Xiao³, Aoxue Wang¹, Yejun Zou¹, Xie Li¹, Xianjun Chen¹, Zhenyu Ju⁷, Wei Jia⁴, Joseph Loscalzo⁸, Yu Sun⁹, Wei Fang¹⁰, Yi Yang¹¹, Yuzheng Zhao¹²

Affiliations

¹ Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing 100730, China.
² Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
³ Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
⁴ Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
⁵ Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.
⁶ Suzhou Ruijin Vitiligo Medical Research Institute, Suzhou 215100, China.
⁷ Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China.
⁸ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁹ Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
¹⁰ Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China. Electronic address: weifang081782@163.com.
¹¹ Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: yiyang@ecust.edu.cn.
¹² Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address: yuzhengzhao@ecust.edu.cn.

PMID: 39413790
DOI: 10.1016/j.cmet.2024.09.011

Abstract

Arginine is one of the most metabolically versatile amino acids and plays pivotal roles in diverse biological and pathological processes; however, sensitive tracking of arginine dynamics in situ remains technically challenging. Here, we engineer high-performance fluorescent biosensors, denoted sensitive to arginine (STAR), to illuminate arginine metabolism in cells, mice, and clinical samples. Utilizing STAR, we demonstrate the effects of different amino acids in regulating intra- and extracellular arginine levels. STAR enabled live-cell monitoring of arginine fluctuations during macrophage activation, phagocytosis, efferocytosis, and senescence and revealed cellular senescence depending on arginine availability. Moreover, a simple and fast assay based on STAR revealed that serum arginine levels tended to increase with age, and the elevated serum arginine level is a potential indicator for discriminating the progression and severity of vitiligo. Collectively, our study provides important insights into the metabolic and functional roles of arginine, as well as its potential in diagnostic and therapeutic applications.

Keywords: arginine exchange landscape; arginine metabolism; highly responsive arginine sensors; point-of-care clinical screening; real-time monitoring.