The latest article published in the Cell sub-journal of East China University of Science and Technology: a new technology for high-performance lactic acid monitoring and imaging

On October 28, Professor Zhao Yuzheng and Professor Yang Yi, School of Pharmacy, East China University of Science and Technology, State Key Laboratory of Bioreactor Engineering, Shanghai Frontier Scientific Research Base of Cell Metabolism Optogenetics Technology, and Director Wang Congrong of Shanghai Fourth People's Hospital cooperated to publish a paper entitled "Ultrasensitive sensors reveal the patiostemporal landscape of" in the international authoritative academic journal Cell Metabolism Lactate Metabolism in Physiology and Disease", reports a high-performance new lactic acid monitoring imaging technology, which realizes in situ, real-time and quantitative dynamic tracking of lactate metabolism at the live, subcellular and in vivo levels, and makes important breakthroughs
in the spatial distribution, regulatory network, drug screening and clinical diagnosis of lactic acid.

Lactate has traditionally been thought to be the "ugly duckling" in metabolic waste and energy metabolism produced by the glycolytic pathway, but this perception is gradually changing
.
A growing body of research shows that lactic acid is an important energy fuel, building block and signaling molecule, and is a metabolic "star" with multiple key roles and plays an important role
in physiological and pathological processes.
However, lactic acid metabolism shows drastic dynamic changes and complex spatial distribution, and traditional biochemical methods are difficult to achieve dynamic tracking
at the living cell and in vivo level.
Therefore, there is an urgent need to establish a new technology
for high-spatiotemporal resolution lactate metabolism monitoring for living cells and in vivo.

Genetically encoded fluorescent probes are a weapon to solve this technical problem
.
Focusing on the international frontier field of cell metabolism monitoring, the research team has developed a series of high-performance metabolic fluorescent probes and "high-throughput" and "panorama" live-cell metabolism monitoring and analysis methods for key intracellular coenzymes NAD(H), NADPH and lactic acid, and the research results have been published in Nature Methods (2017), Nature Metabolism (2021), Nature Protocols (2018; 2016）、Cell Metabolism（2022； 2019；2015； 2011), Developmental Cell (2020), Cell Reports (2022), Science Advances (2021), Blood (2020) and other international authoritative academic journals have become important benchmarks
in this research field 。 This time, based on rational design and directional evolution strategies, the research team obtained the highly specific, high-response, ultra-sensitive lactic acid fluorescent probe FiLa, which has significant advantages in the resolution, accuracy and convenience of monitoring and analysis, which can be described as a blockbuster research
in the field of energy metabolism analysis technology.

High-performance lactic acid detection technology facilitates drug screening and rapid diagnosis of diseases

Using the FiLa probe, the authors first mapped subcellular lactate metabolism
.
Existing textbooks tell us that lactic acid, as a glycolytic product, is localized in the cytoplasm.

At the end of the 90s, researchers discovered the presence of lactate dehydrogenase in mitochondria, so the question of whether lactic acid is present in mitochondria has triggered a series of studies and heated discussions
.
Using the FiLa probe, the research team was the first to report that intranucleal lactate levels are similar to cytoplasmic levels, while mitochondrial lactate levels are much higher than cytoplasm and nuclei
.
This discovery addresses an important scientific question that has been debated in the field for decades, while at the first time leading to the observation that lactic acid in human cells has a richer metabolic fate, thus opening a new window
for the study of lactate metabolism.
Next, the research team established a high-throughput screening method for live-cell level drugs based on FiLa probes, and found that lactic acid is a key hub
for sensing various metabolic activities 。 The research team further used FiLa probe to carry out live animal imaging studies on mice with type I diabetes and type II diabetes, and established a high-throughput clinical sample point-of-care detection technology based on FiLa probe, which measured the lactate levels of adult occult autoimmune diabetes mellitus (type I type I), type II diabetes, maternal hereditary diabetes with deafness (MIDD) and healthy people, respectively, and found that the urine lactate level of MIDD diabetic patients was increased
。 Due to the lack of significant differentiation between the age of onset and clinical manifestations of patients with MIDD, they are often misdiagnosed as type I or type II diabetes, and the discovery of significantly elevated urine lactate may be used as a potential screening marker for the disease, providing an important basis
for clinical diagnosis.

In general, this study not only develops lactic acid metabolism monitoring technology with wide application prospects, solves the long-term controversy about lactic acid metabolism, leads to a series of cutting-edge research questions, but also provides innovative research tools for life medicine fields such as life phenomenon analysis, disease mechanism exploration, innovative drug discovery, and rapid diagnosis of diseases, helping people's lives and health
.

Postdoctoral fellows Li Shu, Wang Aoxue, Zou Yejun, Li Ting, doctoral students Huang Li and Chen Weicai, as well as Zhang Yinan, associate researcher of Shanghai Sixth People's Hospital, and researcher Xu Lingyan of East China Normal University are the main completers of
this research.
Professor Zhao Yuzheng, Professor Yang Yi and Wang Congrong of Shanghai Fourth People's Hospital are the corresponding authors, and our university is the first newsletter
of this article.
This work was strongly supported and helped
by Professor Joseph Loscalzo of Harvard Medical School, Academician Jia Weiping and Professor Jia Wei of Shanghai Sixth People's Hospital, Professor Ma Xinran of East China Normal University, Professor Ju Zhenyu of Jinan University, Professor Zhu Linyong of East China University of Science and Technology, and Professor Zhou Haimeng of Tsinghua University.
The research work has been funded
by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Shanghai Frontier Scientific Research Base of Cell Metabolism Optogenetics Technology, the Medical and Health Science and Technology Innovation Project of the Chinese Academy of Medical Sciences, and the Shanghai Municipal Science and Technology Commission.

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