Mitochondrial long non-coding RNA GAS5 tunes TCA metabolism in response to nutrient stress
Mitochondrial long non-coding RNA GAS5 tunes TCA metabolism in response to nutrient stress
复制标题
线粒体长非编码RNA GAS5调节TCA代谢以应对营养应激
DOI：
10.1038/s42255-020-00325-z
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发表时间：
2021-01-04
影响因子：
20.8
通讯作者：
Lin, Aifu
中科院分区：
文献类型：
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作者：
Sang, Lingjie;Ju, Huai-qiang;Lin, Aifu
长链非编码RNA的定位在调节细胞过程中起着至关重要的作用。除了建立细胞器相关lncRNA的数据库外，Sang等人还确定了lncRNA GAS 5在营养胁迫期间调节三羧酸循环酶的作用。然而，系统地阐明分子如长链非编码RNA（lncRNA）在细胞内稳态和疾病中的亚细胞分布和功能尚未完全实现。在这里，我们揭示了多样性和丰富的亚细胞分布的细胞器相关的lncRNA从线粒体，溶酶体和内质网。其中，我们确定了肿瘤局部lncRNA生长停滞特异性5（GAS 5）作为维持细胞能量稳态的肿瘤抑制因子。从机制上讲，能量应激诱导的GAS5通过破坏三羧酸循环的典型成员富马酸水合酶、苹果酸脱氢酶和柠檬酸合酶的代谢酶串联缔合来调节线粒体三羧酸通量。GAS5与肿瘤中相关的线粒体代谢酶水平呈负相关，并有益于乳腺癌患者的总体生存。总之，我们对亚细胞lncRNA分布的详细注释确定了lncRNA在调节细胞代谢稳态中的功能作用，突出了细胞器相关lncRNA作为操纵细胞代谢和疾病的潜在临床靶点。
The localization of long non-coding RNAs plays a vital role in regulating cellular processes. In addition to compiling a database of organelle-associated lncRNAs, Sang et al. identify a role for the lncRNA GAS5 in regulating tricarboxylic acid cycle enzymes during nutrient stress.Organelles use specialized molecules to regulate their essential cellular processes. However, systematically elucidating the subcellular distribution and function of molecules such as long non-coding RNAs (lncRNAs) in cellular homeostasis and diseases has not been fully achieved. Here, we reveal the diverse and abundant subcellular distribution of organelle-associated lncRNAs from mitochondria, lysosomes and endoplasmic reticulum. Among them, we identify the mitochondrially localized lncRNA growth-arrest-specific 5 (GAS5) as a tumour suppressor in maintaining cellular energy homeostasis. Mechanistically, energy-stress-induced GAS5 modulates mitochondrial tricarboxylic acid flux by disrupting metabolic enzyme tandem association of fumarate hydratase, malate dehydrogenase and citrate synthase, the canonical members of the tricarboxylic acid cycle. GAS5 negatively correlates with levels of its associated mitochondrial metabolic enzymes in tumours and benefits overall survival in individuals with breast cancer. Together, our detailed annotation of subcellular lncRNA distribution identifies a functional role for lncRNAs in regulating cellular metabolic homeostasis, highlighting organelle-associated lncRNAs as potential clinical targets to manipulate cellular metabolism and diseases.