The dual mechanism of m6A demethylase ALKBH5 in regulating energy metabolism during exposure to MC-LR
Abstract Exposure to MC-LR has been shown to cause multiple organ injury, particularly liver injury, and altered energy metabolism is closely linked. As an effective and efficient way to regulate biological gene expression, N(6)-methyladenosine(m6A) modification plays an important role in liver inju...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07791-x |
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| Summary: | Abstract Exposure to MC-LR has been shown to cause multiple organ injury, particularly liver injury, and altered energy metabolism is closely linked. As an effective and efficient way to regulate biological gene expression, N(6)-methyladenosine(m6A) modification plays an important role in liver injury caused by microcystin-LR(MC-LR) exposure. For the first time, we reveal the dual mechanism by which AlkB homolog 5(ALKBH5) regulates energy metabolism through an m6A-YTHDF3-dependent mechanism. After MC-LR exposure, low levels of ALKBH5 increased the m6A modification of Phosphoinositide-3-Kinase Regulatory Subunit 1(PIK3R1) and m6A methylation was located at A1557. PIK3R1-m6A was recognised by YTH N6-Methyladenosine RNA Binding Protein F3(YTHDF3), which reduced the stability of PIK3R1 RNA, thereby inhibiting PIK3R1 expression and ultimately promoting glycolysis. In concert, low-level ALKBH5 inhibit oxidative phosphorylation by down-regulating the expression of Electron Transfer Flavoprotein Dehydrogenase(ETFDH), Electron Transfer Flavoprotein Subunit Alpha(ETFA) and NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 4(NDUFAF4) through an m6A-YTHDF3-dependent mechanism. This dual mechanism has been shown to adversely affect cell survival in MC-LR exposed environments by significantly reducing ATP levels. This study reveals for the first time the signalling pathway and molecular mechanism of MC-LR exposure to liver injury through ALKBH5-mediated m6A modification, providing new protective and therapeutic principles. Subject terms: m6A modification; Oxidative phosphorylation; Glycolysis The mechanism of m6A demethylase ALKBH5 in regulating energy metabolism during exposure to MC-LR. Created with BioRender.com. |
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| ISSN: | 2041-4889 |