Fig. 4

Involvement of mitochondria in the adaptive immune response: Mitochondrial ROS leads to increased production of inflammatory genes such as NF-ĸB, AP-1, and NFAT. In addition, mitochondria provide the essential components for protein synthesis. For example, MDH2 converts malate to oxaloacetate, which yields aspartate, a purine and pyrimidine precursor. Furthermore, SHMT2 offers one-carbon units for purine and thymidine synthesis, aiding T-cell proliferation. Excess lactate from the Warburg effect can convert to acetyl-CoA, which promotes IFN-γ production through histone acetylation. On the other hand, Treg differentiation is mostly dependent on OXPHOS rather than glycolysis; thus, inhibiting the glycolysis pathway lowers Th17 differentiation. During the memory phase, mitochondria join together to generate larger mitochondria. This remodeling relies on the fusion of proteins, including mitofusin-1, mitofusin-2, and OPA1, to increase OXPHOS and maintain SRC. The T cell exhaustion marker PD-1 signaling suppresses mitochondrial biogenesis by inhibiting the expression of PGC1α. Thus, PD-1 signaling inhibition may accelerate glucose absorption and improve mitochondrial metabolic performance. Regarding B cell proliferation, mitochondria activate swiprosin-2, an inner mitochondrial membrane protein that regulates metabolic switching during the transition from pro-B cells to pre-B cells. Memory B cells rely significantly on mitochondria for long-term survival. For instance, memory B cells are more resistant to mitochondrial apoptosis due to increased expression of the Bcl-2 anti-apoptotic proteins. Bcl-2 proteins prevent the release of apoptosis-inducing chemicals, such as cytochrome c and AIF, from the intermembrane gap. On the other hand, M2 macrophages rely extensively on OXPHOS and FAO to perform their tissue-repairing and immunoregulatory functions. Unlike M1 macrophages, L-arginine metabolism in M2 macrophages is regulated by Arg-1, resulting in the generation of L-ornithine and polyamines, which stimulate tissue remodeling and repair. M1 and M2 macrophages'metabolic differences highlight the complex interplay between mitochondrial activity, metabolic pathways, and immune regulation. AP-1; activating protein 1, NFAT; nuclear factor of activated T cells, MDH2; malate dehydrogenase-2, SHMT2; mitochondrial serine hydroxymethyltransferase 2, FOXP3; Forkhead box P3, ETC; electron transport chain, SRC; spare respiratory capacity, AIF; apoptosis-inducing factor, PD1; programmed cell death protein 1, PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1-α