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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 TCA cycle products 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 required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially-derived citrate exported to the cytoplasm is metabolized via ATP citrate lyase (ACL), ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating expression of ACL or the canonical TCA cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells (ESCs) revealed that changes in TCA cycle configuration accompany cell fate transitions. During exit from pluripotency, ESCs 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. |
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