Infect Chemother.  2017 Mar;49(1):10-21. 10.3947/ic.2017.49.1.10.

Mitochondrial Dysfunction and Immune Cell Metabolism in Sepsis

• Park DW
• Zmijewski

• KMID: 2375094
• DOI: http://doi.org/10.3947/ic.2017.49.1.10

Abstract

Sepsis is a life threatening condition mediated by systemic infection, but also triggered by hemorrhage and trauma. These are significant causes of organ injury implicated in morbidity and mortality, as well as post-sepsis complications associated with dysfunction of innate and adaptive immunity. The role of cellular bioenergetics and loss of metabolic plasticity of immune cells is increasingly emerging in the pathogenesis of sepsis. This review describes mitochondrial biology and metabolic alterations of immune cells due to sepsis, as well as indicates plausible therapeutic opportunities.

Keyword

Sepsis; Multi-organ failure; Mitochondria; Immune cell; Metabolism

MeSH Terms

Adaptive Immunity
Biology
Energy Metabolism
Hemorrhage
Metabolism*
Mitochondria
Mortality
Plastics
Sepsis*
Plastics

Figure

• 

  Figure 1 Integration of metabolic pathwaysGlucose is metabolized to pyruvate through the glycolysis. Pyruvate (and fatty acids) enters the mitochondria where they are converted to acetyl-CoA. This enters the Krebs cycle that donates electrons to electron transport chain. Through OxPhos, electrons are sequentially transferred to generate a H+ gradient across the inner mitochondrial membrane, which drives the synthesis ATP. In addition to the glycolysis, cells have the ability to metabolize alternative substrates, such as lipids and glutamine. FAO and glutaminolysis replenish the Krebs cycle intermediates acetyl-CoA and α-ketoglutarate, respectively, thereby fueling OxPhos. PPP generates riboses for nucleotides synthesis.PPP, pentose phosphate pathway; OxPhos, oxidative phosphorylation; FAO, fatty acid β-oxidation; ADP, adenosine diphosphate; ATP, adenosine triphosphate; ETC, electron transport chain.

• 

  Figure 2 Neutrophils anti-microbial action is linked to bioenergeticsNADPH, which is required for production of ROS, is generated in PPP branch of glycolysis or from the oxidation of glutamine derived malate to pyruvate. In this manner, the biochemical pathways of glycolysis and glutaminolysis provide the microbicidal activity to activated neutrophil.PPP, pentose phosphate pathway; ADP, adenosine diphosphate; ATP, adenosine triphosphate; ROS, reactive oxygen species; MPO myeloperoxidase; NOX2, NADPH oxidase 2; HOCI, hypochlorous acid.

• 

  Figure 3 Mitochondria plays a crucial role in regulating neutrophil function.(A) Mitochondrial function in the leading edge supports neutrophil chemotaxis. In infection site, LPS-TLR4 engagement indices mitochondrial depolarization and subsequent inhibition of neutrophil motility and promote pro-inflammatory action. Pro-bactericidal effects are activated by NADPH oxidase activation. Notably, H2O2 is important to bacterial killing and promote neutrophil transition from pro-inflammatory to anti-inflammatory phenotype. (B) Severe sepsis and shock is characterized by accumulation of bacterial products and DAMPs in circulation. LPS inhibits neutrophil chemotaxis and promote pro-inflammatory activation flowed by random adhesion to endothelial cells. Neutrophils extravasation and activation is implicated in tissue injury.ATP, adenosine triphosphate; TLR, Toll-like receptor; LPS, lipopolysaccharide; NADPH, nicotinamide adenine dinucleotide phosphate; DAMPs, damage associated molecular pattern proteins.

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