Modular to cyclic TCA governs hematopoiesis in Drosophila

Abstract

TCA cycle is well known for its role in bioenergetics and also a hub for metabolic exchange, here we identify a developmentally programmed, non-uniform TCA architecture that is required for hematopoietic state transitions in the Drosophila lymph gland. Early blood progenitors operate a modular TCA configuration, in which a CS/mAcon1-derived citrate node preserves progenitor identity, while a Gdh/Kdh mediated -ketoglutarate to succinyl-CoA branch, not succinate, supports proliferative potential. As cells exit the progenitor state and initiate lineage commitment, the cells undergo metabolic reorganization and engage a fully cyclic, Pdh- and Idh-dependent oxidative TCA cycle whose cataplerotic activity keeps the levels of TCA metabolites in check as their excess otherwise induces differentiation. Blocking these metabolic transitions disrupts progenitor homeostasis, compromises proliferative competency of transitional progenitors, and distorts balanced differentiation. These findings establish a developmentally regulated alternative to the traditional TCA cycle and reveals that appropriate engagement of modular versus cyclic TCA modes is required for orchestrating hematopoietic fate transitions. This work highlights TCA topology and not flux alone functions as a core determinant of stemness, proliferation, and lineage progression during hematopoiesis. Significance StatementHematopoietic development requires precise metabolic control to maintain progenitors while enabling their transition into differentiated lineages. We show that the Drosophila lymph gland achieves this through a developmentally programmed switch in TCA-cycle configuration where early progenitors rely on a modular TCA architecture that independently sustains identity and proliferation, whereas later stages require a fully cyclic, oxidative TCA mode to maintain homeostasis and balanced differentiation. Disrupting either phase perturbs hematopoietic organization, demonstrating that TCA topology itself regulates cell-state transitions. These findings reveal TCA architecture as the determinant of hematopoietic fate and provides a conceptual framework relevant to hematopoiesis and also stem cell biology.