Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis
RNA-sequencing was performed to look for transcriptional differences between wild-type and Mpc2-deficient granulocyte-macrophage progenitors immediately following the deletion of Mpc2. Paper abstract: Hematopoietic stem and progenitor cells likely engage specific metabolic pathways to promote homeostasis of downstream mature lineages. We examined hematopoiesis in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. Deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient increase in proliferation of myeloid but not other progenitors. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor-intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, whereas mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, rapid recovery from acute loss of myeloid cells requires a switch to glutaminolysis in progenitors. Overall design: RNA-sequencing of wild-type and Mpc2 knockout granulocyte-macrophage progenitors immediately following Mpc2 deletion