Pivotal Role of Mitochondria in Macrophage Response to Bacterial Pathogens

Abstract

Mitochondria are essential organelles that act as metabolic hubs and signaling platforms within the cell. Numerous mitochondrial functions, including energy metabolism, lipid synthesis, and autophagy regulation, are intimately linked to mitochondrial dynamics, which is shaped by ongoing fusion and fission events. Recently, several intracellular bacterial pathogens have been shown to modulate mitochondrial functions to maintain their replicative niche. Through selected examples of human bacterial pathogens, we will discuss how infection induces mitochondrial changes in infected macrophages, triggering modifications of the host metabolism that lead to important immunological reprogramming.

Keywords: bacterial infection; cell polarization; immunometabolism; macrophage; mitochondria.

Figure 1

Macrophage activation upon bacterial infection. Quiescent macrophages (M0) have the ability to polarize into two antagonist cell types. At early steps of infection, M0 macrophages differentiate into M1 macrophages (upper part) that display a pro-inflammatory profile. They support highly efficient pathogen killing. This phenotype is associated with glycolysis induction. In contrast and later during infection, M0 macrophages can also differentiate into M2 macrophages (lower part). They rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). They help in inflammation resolution.

Figure 2

Macrophage infection affects host metabolic state and can induce an M1 profile. M1 macrophages are characterized by a hyper-activated glycolysis coupled with a limited mitochondrial activity (limited OXPHOS and FAO) upon lipopolysaccharide (LPS) or interferon gamma (IFNγ) activation (left part). The transporter Glut 1 and the glycolytic enzymes hexokinase 2 (HEK2) and phosphofrucotkinase 2 (PFK2) are activated (central part) in a hypoxia-inducible factor 1-α (HIF-1α)-dependent manner. LPS also activates the uncoupling protein 2 (ucp2) transcription via p38 and JNK pathways, leading to a decrease in pyruvate incorporation into TCA cycle. Some pathogens (vacuolar or cytosolic, right part) can use glycolytic derivatives [such as pentose phosphate pathway (PPP) metabolites, amino acids, and lactate] as nutrients to sustain their propagation.

Figure 3

M1 macrophage defenses upon bacterial infection. In M1 macrophages, the mitochondrial TCA cycle is shunted at the isocitrate dehydrogenase (IDH) step, subsequently leading to itaconate formation. The succinate dehydrogenase (SDH) step is also arrested, leading to succinate accumulation and IL-1β transcription increase in a Hif1-α-dependent manner. Decrease in TCA cycle activity efficiency is also responsible for an increase in ΔΨ_m that induces the production of mROS. In bacteria-infected macrophages (left part), phagosomal maturation is responsible for N-acetylglucosamine (GlcNAc) release. GlcNAc binds mitochondrial hexokinase (HK) and induces its cytosolic release that activates NLRP3 inflammasome. mROS also induce NLRP3 activation.