A non-canonical tricarboxylic acid cycle underlies cellular identity

Paige K. Arnold, Benjamin T. Jackson, Katrina I. Paras, Julia S. Brunner, Madeleine L. Hart, Oliver J. Newsom, Sydney P. Alibeckoff, Jennifer Endress, Esther Drill, Lucas B. Sullivan and Lydia W. S. Finley ()
Additional contact information
Paige K. Arnold: Memorial Sloan Kettering Cancer Center
Benjamin T. Jackson: Memorial Sloan Kettering Cancer Center
Katrina I. Paras: Memorial Sloan Kettering Cancer Center
Julia S. Brunner: Memorial Sloan Kettering Cancer Center
Madeleine L. Hart: Fred Hutchinson Cancer Research Center
Oliver J. Newsom: Fred Hutchinson Cancer Research Center
Sydney P. Alibeckoff: Fred Hutchinson Cancer Research Center
Jennifer Endress: Memorial Sloan Kettering Cancer Center
Esther Drill: Memorial Sloan Kettering Cancer Center
Lucas B. Sullivan: Fred Hutchinson Cancer Research Center
Lydia W. S. Finley: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 603, issue 7901, 477-481

Abstract: Abstract 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 activity1,2. 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 of ATP 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.

Date: 2022
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DOI: 10.1038/s41586-022-04475-w

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