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  3. Ultrasensitive sensors reveal the spatiotemporal landscape of lactate metabolism in physiology and disease

Ultrasensitive sensors reveal the spatiotemporal landscape of lactate metabolism in physiology and disease

  • Cell Metab. 2023 Jan 3;35(1):200-211.e9. doi: 10.1016/j.cmet.2022.10.002.
Xie Li 1,  Yinan Zhang 2,  Lingyan Xu 3,  Aoxue Wang 1,  Yejun Zou 1,  Ting Li 1,  Li Huang 4,  Weicai Chen 4,  Shuning Liu 4,  Kun Jiang 4,  Xiuze Zhang 4,  Dongmei Wang 3,  Lijuan Zhang 4,  Zhuo Zhang 1,  Zeyi Zhang 4,  Xianjun Chen 1,  Wei Jia 2,  Aihua Zhao 2,  Xinfeng Yan 5,  Haimeng Zhou 6,  Linyong Zhu 4,  Xinran Ma 3,  Zhenyu Ju 7,  Weiping Jia 2,  Congrong Wang 8,  Joseph Loscalzo 9,  Yi Yang 10,  Yuzheng Zhao 11
Affiliations

Affiliations

  • 1 Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing 100730, China; CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Center for Translational Medicine, The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 4 Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 5 Translational Medical Center for Stem Cell Therapy, Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 6 Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, 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 Endocrinology & Metabolism, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200434, China. Electronic address: crwang@tongji.edu.cn.
  • 9 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: yiyang@ecust.edu.cn.
  • 11 Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, 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: 36309010 DOI: 10.1016/j.cmet.2022.10.002
Abstract

Despite its central importance in cellular metabolism, many details remain to be determined regarding subcellular lactate metabolism and its regulation in physiology and disease, as there is sensitive spatiotemporal resolution of lactate distribution, and dynamics remains a technical challenge. Here, we develop and characterize an ultrasensitive, highly responsive, ratiometric lactate sensor, named FiLa, enabling the monitoring of subtle lactate fluctuations in living cells and Animals. Utilizing FiLa, we demonstrate that lactate is highly enriched in mammalian mitochondria and compile an atlas of subcellular lactate metabolism that reveals lactate as a key hub sensing various metabolic activities. In addition, FiLa sensors also enable direct imaging of elevated lactate levels in diabetic mice and facilitate the establishment of a simple, rapid, and sensitive lactate assay for point-of-care clinical screening. Thus, FiLa sensors provide powerful, broadly applicable tools for defining the spatiotemporal landscape of lactate metabolism in health and disease.

Keywords

highly responsive lactate sensors; lactate metabolism; point-of-care clinical screening; real-time monitoring; subcellular lactate landscape.

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