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Mitochondria, Microglia, and the Immune System-How Are They Linked in Affective Disorders?


Mitochondria, Microglia, and the Immune System-How Are They Linked in Affective Disorders?

Carsten Culmsee et al. Front Psychiatry.


Major depressive disorder (MDD) is a severe mood disorder and frequently associated with alterations of the immune system characterized by enhanced levels of circulating pro-inflammatory cytokines and microglia activation in the brain. Increasing evidence suggests that dysfunction of mitochondria may play a key role in the pathogenesis of MDD. Mitochondria are regulators of numerous cellular functions including energy metabolism, maintenance of redox and calcium homeostasis, and cell death and therefore modulate many facets of the innate immune response. In depression-like behavior of rodents, mitochondrial perturbation and release of mitochondrial components have been shown to boost cytokine production and neuroinflammation. On the other hand, pro-inflammatory cytokines may influence mitochondrial functions such as oxidative phosphorylation, production of adenosine triphosphate, and reactive oxygen species, thereby aggravating inflammation. There is strong interest in a better understanding of immunometabolic pathways in MDD that may serve as diagnostic markers and therapeutic targets. Here, we review the interaction between mitochondrial metabolism and innate immunity in the pathophysiology of MDD. We specifically focus on immunometabolic processes that govern microglial and peripheral myeloid cell functions, both cellular components involved in neuroinflammation in depression-like behavior. We finally discuss microglial polarization and associated metabolic states in depression-associated behavior and in MDD.

Keywords: immune cells; immune system; immunometabolism; major depressive disorder; metabolic pathways; microglia; mitochondria; neuroinflammation.


Figure 1
Figure 1
Mitochondrial involvement in microglial activation and inflammatory signaling. Microglial activation pathways and inflammatory cytokine release are initiated by the binding of pathogen- or damage-associated molecular patterns (PAMPs/DAMPs) to intracellular or membrane-bound pattern recognition receptors (PRR), such as NOD-like receptors (NLR) or Toll-like receptors (TLR). This triggers NLRP3 and Caspase-1 assembly to form the inflammasome leading to the processing of pro-IL-1β as well as pro-IL-18 to active IL-1β and IL-18, respectively. In addition, oxidized mitochondrial DNA (ox-mtDNA) and mitochondrial reactive oxygen species (ROS) are canonical activators of inflammasome formation. Tumor necrosis factor (TNF) and Interleukin-6 (IL-6) are generated via nuclear factor NF-κB-dependent transcriptional activation. The oxidation of L-arginine (L-Arg) by inducible nitric oxide synthase (iNOS) produces NO (Nitric oxide), which in turn inhibits oxidative phosphorylation (OXPHOS) shifting the energy metabolism of the cell toward glycolysis. Ca2+ influx via L-type calcium channels (LTCC) and ATP-binding purinoceptors (P2X7) results in the loss of mitochondrial membrane potential (ΔΨm), enhanced mitochondrial ROS formation and further contributes to inflammasome formation and pro-inflammatory activation of microglia.

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