Mitochondria as central hub of the immune system

Abstract

Nearly 130 years after the first insights into the existence of mitochondria, new rolesassociated with these organelles continue to emerge. As essential hubs that dictate cell fate, mitochondria integrate cell physiology, signaling pathways and metabolism. Thus, recent research has focused on understanding how these multifaceted functions can be used to improve inflammatory responses and prevent cellular dysfunction. Here, we describe the role of mitochondria on the development and function of immune cells, highlighting metabolic aspects and pointing out some metabolic- independent features of mitochondria that sustain cell function.

Keywords: And immune cells; Cell fate; Immunometabolism; Mitochondrial function.

Fig. 1

Immature and mature neutrophils have different metabolic requirements. A. In the presence of normal glucose levels, immature neutrophils undergo autophagy to a proper maturation through FAO associated with OXPHOS. In the same way, during a low glucose levels context (tumoral environment), immature neutrophils prioritize FAO associated with OXPHOS to increase NADPH levels and consequently oxidants production. Excess of oxidants leads to T cell inhibition, contributing to tumor growth. B. Mature neutrophils prioritize aerobic glycolysis and generate NADPH from PPP. NADPH is the Nox2 substrate to produce oxidants inside the phagosome and crucial to eliminate phagocyted pathogens. Oxidants from Nox2 are also important to NETs formation from genomic DNA while mtROS are important to mitochondrial NETs production. Intracellular Ca²⁺ levels stimulate mitochondrial ATP production by the mTOR pathway. The ATP acts in an autocrine way by binding the P2Y2 receptors in the neutrophils stimulating intracellular Ca²⁺ mobilization and chemotaxis. Mitochondrial fission also contributes to neutrophil chemotaxis.

Fig. 2

Metabolism of macrophages. A. Under LPS and IFN-γ stimuli, macrophages preferentially use glucose to produce lactate. In the mitochondria, citrate can be exported and used to produce fatty acids and itaconate. The mitochondria increase the production of oxidants and succinate, which are capable to stabilize the transcription factor HIF-1α in the cytosol, triggering the transcription of HIF-1α-target genes. The M1 macrophage is characterized by mitochondria fission. B. Metabolism of M2 macrophages. Alternatively activated macrophages (M2) use glucose and glutamine to feed the TCA cycle and produce ATP by oxidative phosphorylation. These cells are known to have elongated mitochondria, and consequently more efficient energy production. The use of fatty acid oxidation and glycolysis by M2 macrophages are under review in the literature.

Fig. 3

Metabolism of dendritic cells and T lymphocytes. Inflammatory signals drive glycolysis, increasing glucose uptake and glycogenosis in DCs. The conversion from glucose to pyruvate increases citrate levels in the mitochondria, which can be exported to the cytosol. The PPP generates NADPH, used in the FAS. FAS are used to generate membranes to the endoplasmic reticulum and Golgi complex, in an NADPH-dependent manner, both necessary to increase protein synthesis. Dendritic cells process antigens and present them using the MHC at the cell surface where they can be recognized by the TCR. This event engages ROS production, which facilitates the activation of nuclear factor of activated T cell (NFAT) activation. This transcription factor induces IL-2, a T cell growth cytokine.

Fig. 4

Essential metabolism and mitochondrial regulation on B cells (A) and Antibody-Secreting Cells (B). A. B cells are activated through T cell-independent or -dependent mechanisms. B cell activation increases both aerobic glycolysis and OXPHOS rates, enhancing the expression of the glucose transporter Glut1 and mitochondrial mass. Part of the TCA cycle fueling is used to de novo lipid biosynthesis via citrate transport from the mitochondria into the cytoplasm. B cell activation promotes both oxidants and antioxidants production, which the balance regulates B cell survival, effector functions and cell fate. Higher mtROS levels are important for sustaining both mitochondrial activity and mass, activating the CSR. On the other hand, lower mtROS levels were directly associated with plasma cell differentiation. Moreover, B cell activation also increases the mitochondria number and change their anatomy from an elongated to a rounded shape. Recently, CpG-stimulated TLR9 in B cells causes mtDNA releasing into the extracellular environment and its associated in stimulating anti-viral responses via type I IFN production. B. ASCs have high metabolic demand in order to produce antibodies. Part of the glucose is used to glycosylate antibodies and intracellular membrane expansion. Higher antioxidant activity is associated with increased IgM secretion by ASCs. Different subtypes of plasma cells show different metabolic profiles. LLPCs show increased glucose uptake, CD98 amino acid transporter expression and autophagosome mass compared to SLPCs. a.a: amino acids. ASC: Antibody-Secreting Cell, BCR, B Cell Receptor, CSR, Class-Switch Recombination, FAS, Fatty Acid Synthesis, GSH, Glutathione, LLPCs, Long-Lived Plasma Cells, OXPHOS, Oxidative Phosphorylation, PPP, Pentose Phosphate Pathway, SLPCs, Short-Lived Plasma Cells, TCR, T Cell Receptor, TLR, Toll-Like Receptor, TCA, Tricarboxylic Acid Cycle, xCT, Cystine/glutamate transporter.