Challenges and opportunities in targeting metabolism

Kivanç Birsoy教授关于细胞代谢未来研究方向的看法：

    在过去的十年中，细胞代谢领域经历了巨大的发展。这种发展主要是由人们对了解癌细胞代谢变化的兴趣所驱动的，但它也对其他领域产生了积极影响，如代谢的基础研究、神经科学和免疫学等。在我看来，一个需要进一步探索的领域是代谢通路的分区化。细胞器在细胞功能和代谢中起着至关重要的作用，但真核细胞如何在其细胞器中维持许多代谢物的可用性在很大程度上尚未被探索。细胞器代谢组学和遗传筛选的进展为揭示真核生物细胞器代谢的复杂性提供了清晰的途径，包括三个主要领域：代谢通路的组成部分、调控和生理功能。首先，一个关键的任务是定义细胞和亚细胞代谢的组成部分。令人惊讶的是，许多细胞器中的酶和小分子转运体的相当一部分底物仍然未知。
    其次，营养分子感知是生物学中一个非常富有成果的领域，具有重要的转化意义，如胆固醇代谢（固醇调节元件结合蛋白SREBP）和氨基酸代谢（雷帕霉素靶蛋白TOR）。然而，我们对细胞器如何维持代谢物稳态和感知其营养分子水平的变化仍然知之甚少。最后，鉴于许多亚细胞成分与先天性代谢缺陷、癌症和神经退行性疾病的相关性，探索不同细胞类型（如免疫细胞和干细胞）的亚细胞代谢也具有巨大的治疗潜力。

The future of cellular metabolism is compartmentalized

Kivanç Birsoy：  Over the past decade, the field of cellular metabolism has experienced tremendous growth. This growth has been primarily driven by the interest in understanding changes in the metabolism of cancer cells, but it has also had a positive impact on other fields, such as fundamental metabolism, neuroscience, and immunology. In my opinion, one area that requires further exploration is metabolic compartmentalization. Organelles play a crucial role in cellular functions and metabolism, but how eukaryotic cells maintain the availability of many metabolites in their organelles is largely unexplored. Advancements in organellar metabolomics and genetic screening offer a clear path to unraveling the intricacies of organellar metabolism in eukaryotes in three major areas: components, regulation, and physiology. Firstly, a crucial task is defining the components of cellular and subcellular metabolism. Surprisingly, a considerable fraction of substrates for many organellar enzymes and small-molecule transporters remains unknown. 

    Secondly, nutrient sensing has been an exceptionally fruitful area of biology with major translational implications, as seen in the case of cholesterol (SREBP) and amino acid metabolism (TOR). However, we still know little about how organelles maintain metabolite homeostasis and sense changes in their nutrient availability. Lastly, given the relevance of many subcellular components in inborn errors of metabolism, cancer, and neurodegeneration, exploring the subcellular metabolism of different cell types (e.g., immune cells and stem cells) holds immense therapeutic potential.

代谢物与活性氧作为信号分子

Metabolites and ROS as signaling molecules 

 Navdeep S. Chandel：Metabolism has evolved beyond its traditional understanding of catabolism and anabolism. Over the past 20 years, metabolism has been recognized as a central player in both physiology and pathology, independently of its classical roles. This shift in perspective underscores the role of metabolites and oxidative metabolism byproducts, particularly ROS (reactive oxygen species), as signaling molecules that modulate health and disease. To decode this idea, it is essential to develop new tools. First, we need innovative techniques to identify the precise targets of metabolites and ROS, such as superoxide, hydrogen peroxide, and lipid hydroperoxides, in both healthy and disease states. This is largely uncharted territory. The question remains: how does a specific ROS or metabolite pinpoint its target to influence physiological reactions? Growing evidence suggests that any imbalance in ROS or metabolites can lead to disease. Understanding the specificity of these targets might pave the way for a new generation of treatments. Second, by harnessing genetic and pharmacological tools, we can causally prove the distinct roles played by different ROS and metabolites in controlling physiology and disease onset. The upcoming progress in new methods for detecting and adjusting ROS and distinct metabolites promises a transformative understanding in the coming decade. What excites me as we move forward is the application of these tools in neuroscience. Changes in metabolism and ROS are linked to many neurological diseases. However, it is not clear whether these alterations in metabolism or ROS initiate or result from brain disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. The identification of metabolic changes and ROS targets that cause particular brain disorders could provide new therapeutics for these devastating diseases.

代谢物信号与代谢通讯

Metabolite signaling and metabolic communication 

Sarah-Maria Fendt：Metabolism has been classically considered in health and disease for its function in ensuring organismal glucose homeostasis and cellular energy production, as well as in providing building blocks for proliferation. However, recent findings highlight an additional role of metabolism and metabolites in signaling and as communication signals. This includes but is not limited to metabolites regulating epigenetics and cell signaling through posttranslational modifications, metabolites binding or being sensed by regulatory proteins, and enzymes having non-catalytic functions. Most principles and mechanisms of metabolite signaling were discovered through research on disease conditions, such cancer and diabetes. Yet, metabolic alterations in disease conditions are often based on normal cellular functions. Thus, it will be important to define whether and how metabolite signaling is important for normal organismal processes (such as development, maturation, reproduction, and aging) and, as a consequence, the disease conditions associated with these processes. Moreover, it will be exciting to determine how organismal physiology, which is dependent, for example, on lifestyle (including diet and exercise), might affect metabolite signaling and metabolic communication in health and disease. Technological advances in single-cell and spatial analysis of metabolism combined with systems biology approaches for data integration are expected to accelerate the discovery and underlying molecular mechanisms of metabolite signaling and metabolic communication.

宿主-微生物在代谢层面的相互作用

Host-microbe metabolic interaction 

Xiaoling Li：Recent advances in biological research have increasingly shown that many organisms do not function as individually isolated entities. The concept of the holobiont, defined as the host organism and its associated microbial communities, has gained significant attention in various fields, ranging from environmental sciences to biomedical research. In particular, the complex metabolic interaction between mammals, including humans, and their gut microbiota has emerged as one of the most exciting research topics in the metabolism field.

The host-microbe metabolic interaction is crucial for the health and function of both the host and the microbes. The host provides diverse niches, such as the gut mucosal surface, and nutrients for the survival of the microbes. Conversely, the microbes evolved a remarkably diverse set of metabolic networks that allow them to thrive in constantly changing niche environments. Many of their metabolic products affect host physiology and pathology. For instance, gut microbes synthesize many vitamins, essential nutrients, and signaling molecules that are fundamental in shaping the host immune system and influencing the host central nervous system. Consequently, gut dysbiosis has been frequently associated with various pathological conditions, such as cancer, autoimmune diseases, neurodegenerative diseases, autism, and depression.

In my opinion, several topics in the field of host-microbe metabolic interactions demand close attention. These topics include microbe-immune system crosstalk, the gut-brain axis, the maternal-fetal gut microbiota axis, microbial engineering, and microbiome intervention for therapeutic application. The key challenges in the field include overcoming intrinsic complexity and variability to decipher specific host-microbe metabolic interactions, distinguishing correlation from causality, increasing reproducibility, and improving data integration and analysis.

详见：DOI: https://doi.org/10.1016/j.chembiol.2023.08.016 

参考资料：https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00288-X