ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control

• Published in: Cell reports (Cambridge) Vol. 42; no. 10; p. 113163
• Main Authors: Gao, Yimeng, Zimmer, Joshua T., Vasic, Radovan, Liu, Chengyang, Gbyli, Rana, Zheng, Shu-Jian, Patel, Amisha, Liu, Wei, Qi, Zhihong, Li, Yaping, Nelakanti, Raman, Song, Yuanbin, Biancon, Giulia, Xiao, Andrew Z., Slavoff, Sarah, Kibbey, Richard G., Flavell, Richard A., Simon, Matthew D., Tebaldi, Toma, Li, Hua-Bing, Halene, Stephanie
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 31.10.2023; Cell Press; Elsevier
• Subjects: ALKBH5; ATP production; CP: Molecular biology; CP: Stem cell research; energy metabolism; hematopoietic stem and progenitor cells; leukemia; m6A modification; oxidative phosphorylation; OXPHOS; RNA stability; stress hematopoiesis; RNA stability; leukemia; m6A modification; ALKBH5; stress hematopoiesis; CP: Stem cell research; hematopoietic stem and progenitor cells; CP: Molecular biology; ATP production; OXPHOS; energy metabolism; oxidative phosphorylation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113163

N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m6A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia. [Display omitted] •Loss of ALKBH5 attenuates hematopoietic fitness in response to stress•ALKBH5 regulates the stability of Ogdh mRNA and of other metabolic enzymes•L-2-HG accumulates in response to OGDH downregulation and attenuates the energy metabolism•L-2-HG inhibits proliferation of both normal and malignant hematopoietic cells Gao et al. find that ALKBH5 regulates hematopoietic stem and progenitor cell fitness in response to stress. ALKBH5 modulates energy metabolism by controlling stability of Ogdh and other metabolic enzyme transcripts. Accumulation of L-2-HG further inhibits the energy metabolism of hematopoietic cells. These findings provide insights on ALKBH5 in hematopoiesis.