Fig. 4

Autophagy in NK cell development and functionality. The autophagy process drives Hematopoietic Stem Cell (HSCs) differentiation into Common Lymphoid Precursors (CLP) and gains less importance in the generation of NK cell Precursors (NKP). In the stage of immature NK cells (iNK), phosphorylation of Forkhead box O (FoxO) 1 protein mediates its translocation from the nucleus to the cytosol and induces autophagy through interaction with ATG7 in the phagophore. FoxO1 is lost in mature NK cells (mNK) and autophagy is effectively reduced (green lines follow the role of autophagy in NK cell development). At steady state (freshly isolated NK cells), both phenotypes of mNK cells exhibit lower autophagy at the basal level, tubular mitochondria, and dependence on glycolysis and OXPHOS for their metabolism. After activation, the metabolism of the immunomodulatory phenotype (CD56^bright/CD16^dim) does not undergo metabolic reprogramming and shows greater dependence on OXPHOS than glycolysis. On the other hand, activation of cytotoxic phenotype (CD56^dim/CD16.^bright) induces metabolic reprogramming to fuel cytolytic activities, and glycolysis gains more importance after NK-activating Receptors (NKRs)-mediated activation, while OXPHOS and citrate-malate shuttle fuel cytokines-mediated activation. In this context, autophagy is reduced during the proliferation stage of activated NK cells, and metabolic reprogramming is supported by DRP1-mediated mitochondrial fragmentation. In the latter stages of activation, fragmented mitochondria can be recycled through BNIP3/BNIP3L-mediated mitophagy to generate memory NK cells, and OPA-1-mediates mitochondrial fusion for their biogenesis. Fragmented mitochondria alter metabolic fitness in the absence of mitophagy, leading to apoptosis of NK cells. The figure is created with “BioRender.com”