The roles of lactate and the interplay with m6A modification in diseases

• Published in: Cell biology and toxicology Vol. 40; no. 1; p. 107
• Main Authors: Tang, Fajuan, Xiao, Dongqiong, Li, Xihong, Qiao, Lina
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 02.12.2024; Springer Nature B.V
• Subjects: Biochemistry; Biological activity; Biomedical and Life Sciences; Cell Biology; Energy resources; Enzymes; Epigenetics; Fibrosis; Glycolysis; Hemorrhage; Histones; Lactic acid; Life Sciences; Liver cancer; Liver diseases; Lung cancer; Lung diseases; Lymphocytes; Lymphocytes T; Macrophages; Myocardial ischemia; N6-methyladenosine; Natural killer cells; Pharmacology/Toxicology; Post-transcription; Proteins; Review; Sepsis; Signal transduction; Glycolysis; A modification; Lactate; M; Lactylation
• ISSN: 1573-6822; 0742-2091; 1573-6822
• DOI: 10.1007/s10565-024-09951-9

Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m 6 A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m 6 A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m 6 A modifications by enhancing the transcriptional expression levels of m 6 A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m 6 A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m 6 A alterations to impact lactate levels and subsequently affect lactylation processes. Graphical abstract 1. Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation, immune suppression, activating signal transduction, and serving as an energy substrate. 2. Lactate-induced lactylation of histone or non-histone can regulate downstream targets by influencing the transcription and activity of m 6 A-RRE. 3. m 6 A-RRE-mediated modifications can affect key enzymes in the glycolytic pathway or MCT4, impacting lactate levels.