Mitochondrial remodeling controls innate immune effector function in Drosophila hemocytes

Drosophila larval hemocytes, analogous to vertebrate myeloid cells, are central to innate immunity. Despite advances in characterizing hemocyte functions via genetic and biochemical analyses, their metabolic characteristics remain poorly understood. Here, we analyzed metabolic parameters of larval hemocytes across developmental stages, genotypes, and immune activation states using metabolic measurements and single-cell transcriptomics. Our results reveal that hemocytes predominantly rely on mitochondrial respiration for ATP production under homeostasis, with minimal glycolysis. Proliferation or immune activation, particularly lamellocyte differentiation, enhance mitochondrial activity and metabolic flexibility, accompanied by mitochondrial structural remodeling and upregulation of sugar metabolism genes. Functional lamellocytes modulate mitochondrial fission through Drp1 and utilize glucose and trehalose to fuel mitochondrial respiration, which are essential for effective immune responses. Together, these findings provide a comprehensive profile of hemocyte metabolism and highlight the dynamic interplay between mitochondrial metabolism and innate immunity in invertebrate immune cells.