ALKBH5 通过m6A修饰介导的RNA稳定性控制，调控造血干细胞和前体细胞的能量代谢。
ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.
发表日期：2023 Sep 23
作者：
Yimeng Gao, Joshua T Zimmer, Radovan Vasic, Chengyang Liu, Rana Gbyli, Shu-Jian Zheng, Amisha Patel, Wei Liu, Zhihong Qi, Yaping Li, Raman Nelakanti, Yuanbin Song, Giulia Biancon, Andrew Z Xiao, Sarah Slavoff, Richard G Kibbey, Richard A Flavell, Matthew D Simon, Toma Tebaldi, Hua-Bing Li, Stephanie Halene
来源：
Stem Cell Research & Therapy
摘要：
N6-甲基腺苷(m6A) RNA修饰控制着许多细胞过程。这些转录后调控机制在造血过程中的作用尚未完全阐明。我们在这里展示了m6A去甲基酶alkB同源物5(ALKBH5)以m6A依赖性方式调控线粒体ATP产生并调节造血干细胞和前体细胞(HSPC)的适应性。ALKBH5的缺失导致RNA甲基化增加，氧化戊酸脱氢酶(Ogdh)信使RNA的不稳定性增加，OGDH蛋白水平降低。OGDH的可用性有限，减慢三羧酸循环(TCA循环)，导致α-酮戊二酸(α-KG)积累，α-KG转化为L-2-羟基戊二酸(L-2-HG)。L-2-HG抑制了小鼠和人类造血细胞的能量产生。受损的线粒体能量产生给HSPC带来竞争劣势并限制了Mll-AF9诱导的白血病的克隆性。我们的研究揭示了一种RNA m6A去甲基酶ALKBH5调控代谢酶转录本稳定性的机制，从而控制造血和白血病中的能量代谢。版权所有 © 2023 作者。由Elsevier Inc.出版。保留所有权利。
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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.