Figure 1. Key metabolic pathways and their link with the complement system.

Glycolysis, braking down glucose to pyruvate, is yielding low amounts of ATP, yet provides important intermediary metabolites for anabolic reactions and shapes T cell immune functioning. In mitochondria, full oxidation of pyruvate greatly increases the bioenergetic efficiency of cells. C3b–CD46-medited signaling enhances both glycolysis and mitochondrial respiration (1). Oxygen is toxic and inevitably linked with oxidative molecular damage brought by reactive oxygen species (ROS). However, evolution has incorporated ROS as indispensible signaling molecules, and triggering intracellular C5aR1 via C5a during T cell activation impacts on oxygen metabolism and mediates increased production of ROS (2). Mitochondria are furthermore key organelles in orchestrating programmed cell death, which is triggered by the release of cytochrome c and increased ROS production. In T cell homeostasis, complement drives pro-survival pathways. Specifically, C3a generated intracellularly binds it receptor, C3aR, expressed on lysosomes, thereby maintaining constant low-level activation of the mechanistic target of rapamycin (mTOR), which in turn controls glycolysis and mitochondrial function and biogenesis (3). Yet, context specifically, complement also plays critical roles in the regulation of apoptosis: While C3b–CD46-mediated signals counteract apoptosis in stimulated cells via Bcl-2 expression induction (4), local generation of C5a can activate the same anti-apoptotic Bcl-2 pathway but also promote apoptosis via autocrine C5aR1 signaling via the extracellular signal regulated kinase (ERK) pathway (5). Of note, the role(s) of the alternative C5aR2 in these pathways is currently least well understood. Gluc=glucose; G6P=glucose-6-phosphate; F1,6BP=fructose,1,6,-bisphosphate; G3P=glyceraldehyde-3-phosphate; Pyr=pyruvate; Lac=lactate; TCA=tricarboxylic acid cycle; ETC=electron transport chain.