The role of the electron transport chain in immunity

Abstract

The electron transport chain (ETC) couples oxidative phosphorylation (OXPHOS) with ATP synthase to drive the generation of ATP. In immune cells, research surrounding the ETC has drifted away from bioenergetics since the discovery of cytochrome c (Cyt c) release as a signal for programmed cell death. Complex I has been shown to generate reactive oxygen species (ROS), with key roles identified in inflammatory macrophages and T helper 17 cells (TH17) cells. Complex II is the site of reverse electron transport (RET) in inflammatory macrophages and is also responsible for regulating fumarate levels linking to epigenetic changes. Complex III also produces ROS which activate hypoxia‐inducible factor 1‐alpha (HIF‐1α) and can participate in regulatory T cell (Treg) function. Complex IV is required for T cell activation and differentiation and the proper development of Treg subsets. Complex V is required for TH17 differentiation and can be expressed on the surface of tumor cells where it is recognized by anti‐tumor T and NK cells. In this review, we summarize these findings and speculate on the therapeutic potential of targeting the ETC as an anti‐inflammatory strategy.

Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection

“…Both the transcriptomic data and the in vitro assays indicated the role of complex I, III, and IV as essential components of the electron transport chain for generation of ATP and cellular energy requirements. Complexes I and III have a role in ROS production and are essential in inflammatory macrophages and T helper 17 (T H 17) cells while also playing a vital role in lymphocyte activation, proliferation, and differentiation ( Yin & O’Neill, 2021 ). Recently, it has been shown that complex III is crucial for the suppressive function of Tregs ( Weinberg et al, 2019 ).…”

Proteomics Analysis of Aqueous Humor and Rejected Graft in Pig-to-Non-Human Primate Corneal Xenotransplantation

“…MHC I-processing-related proteins such as Rho GTPase-activating protein 45 (ARHGAP45) and protein disulfide-isomerase (P4HB, PDIA3) are involved in xenogeneic rejection, with a high betweenness centrality ( 50 , 51 ). Metabolism of T cells or macrophages through ETCs linking oxidative phosphorylation is closely related to alloimmune responses ( 52 – 54 ). Proteins such as “vesicle-mediated transport,” allograft inflammatory factor 1 (AIF1), clathrin light chain (CLTA), mannose-6-phosphate receptor (M6PR), PLCG2, STX8, and VAV1 are related to immune responses such as allograft rejection, B-cell maturation, lytic granule trafficking in cytotoxic T cells, and TCR-induced integrin clustering ( 12 , 55 – 59 ).…”

Editorial: Highlights for Cardiovascular Therapeutics in 2021 – Trained Immunity, Immunometabolism, Gender Differences of Cardiovascular Diseases, and Novel Targets of Cardiovascular Therapeutics

“…Of note, we recently reported that CD4 + Foxp3 + regulatory T cells (Tregs) have many active innate immunity pathways ( 29 , 30 ), and can sustain their immunosuppressive functions ( 31 ) in a proinflammatory atherogenic environment, although Tregs plasticity in atherosclerosis has been reported ( 32 , 33 ). It has been reported that increased energy metabolism pathways and electron transport chain ( 34 ), including glycolysis, acetyl-CoA generation, mevalonate synthesis, glutaminolysis, and epigenetic modification ( 11 , 35 ), contribute significantly to the establishment of TI. Extensive characterization of TI relative to CVD would provide novel insights into CVD pathogenesis and new therapeutic targets.…”