Research on the mechanism of lactic acid regulating autophagy has been progressed

Recently, Cheng Xiawei, Zhao Yuzheng, Yang Yi and other researchers of the School of Pharmacy and State Key Laboratory of Bioreactor Engineering of East China University of Science and Technology have made new progress in the study of the regulatory mechanism of autophagy, and related research has been published in Science Advances.

Effects of lactic acidification on muscle motor homeostasis. Photo courtesy of East China Institute of Technology

Autophagy is an important process for eukaryotes to rotate intracellular substances. Autophagy plays an important role in physiological and pathological processes, including adaptation to metabolic stress, clearance of protein aggregates and damaged organelles, preimplantation of embryos, aging, neurodegenerative diseases, tumorigenesis and development, etc. Autophagy regulation and its role in physiology and pathology have always been research hotspots in this field.

In this study, the researchers experimentally found that a kinase (ULK1) enhances its activity by phosphorylating lactate dehydrogenase A (LDHA) and promotes lactic acid secretion. Lactic acid mediates lactation modification of phosphatidylinositol kinase type III (Vps34) lysine under the catalysis of acyltransferase. The lactic acidation modification of VPS34 significantly promoted the interaction of its complex subunits and increased its kinase activity, thereby promoting autophagy and endosomal degradation pathway.

In addition, this study elucidates the effect of Vps34 lactation on muscle motor homeostasis and tumor progression through mouse muscle motility models and clinical tumor samples. In the physiological state, muscle lactation occurs during strenuous exercise, which improves the level of autophagy of muscle tissue cells and maintains the homeostasis of muscle tissue in the state of exercise. In the pathological state, the high level of lactic acid produced by aerobic glycolysis of tumor tissue is used as a signaling molecule to improve tumor cell autophagy and promote tumor progression by regulating its lactation.

In summary, the results elucidate the molecular mechanism of ULK1 phosphorylation in regulating LDHA activity, elucidate the effect of lactic acid-mediated Vps34 on autophagy and endosomal-lysosomal degradation pathways, reveal the effect of Vps34 lactation on muscle motor homeostasis and tumor progression, integrate glycolysis regulatory pathway and autophagy regulatory pathway, and show the diversification and complexity of autophagy regulation in higher mammalian cells. (Source: China Science News, Zhang Shuanghu, Li Chenyang)

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