A non-canonical tricarboxylic acid cycle underlies cellular identity

被引：172

作者：

Arnold, Paige K. ^{[1
,2
]}

Jackson, Benjamin T. ^{[1
,2
]}

Paras, Katrina, I ^{[1
,3
]}

Brunner, Julia S. ^{[1
]}

Hart, Madeleine L. ^{[4
]}

Newsom, Oliver J. ^{[4
]}

Alibeckoff, Sydney P. ^{[4
]}

Endress, Jennifer ^{[1
,3
]}

Drill, Esther ^{[5
]}

Sullivan, Lucas B. ^{[4
]}

Finley, Lydia W. S. ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Cell Biol Program, 1275 York Ave, New York, NY 10021 USA

[2] Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY USA

[3] Cornell Univ, Weill Cornell Grad Sch Med Sci, New York, NY 10021 USA

[4] Fred Hutchinson Canc Res Ctr, Human Biol Div, 1124 Columbia St, Seattle, WA 98104 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

来源：

NATURE | 2022年 / 603卷 / 7901期

基金：

美国国家卫生研究院;

关键词：

METABOLIC DEPENDENCIES; PLURIPOTENCY; MITOCHONDRIA; INHIBITION; REPRESSION; OXIDATION; STATE;

D O I：

10.1038/s41586-022-04475-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity(1,2). How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression ofATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.

引用

页码：477 / +

页数：25

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