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

Abstract

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.

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

“…Both responses require rapid energy production which is produced when microglia undergo the metabolic switch to glycolysis . Glycolysis allows energy production and uptake of essential nutrients to support the rapid changes required by “activated” microglia in response to a stimulus, such as phagocytosis, proliferation, migration, and induction of protein synthesis for cytokine and chemokine secretion . Indeed, we identified the ability of the TREM2 variant expressing iPS‐Mg to undergo a normal switch in metabolism from a homeostatic, surveillance profile supported by oxidative phosphorylation, to one in which glycolysis is impaired.…”

“…26,32 Glycolysis allows energy production and uptake of essential nutrients to support the rapid changes required by "activated" microglia in response to a stimulus, such as phagocytosis, proliferation, migration, and induction of protein synthesis for cytokine and chemokine secretion. 3,[42][43][44] Indeed, we identified the ability of the TREM2 variant expressing iPS-Mg to undergo a normal switch in metabolism from a homeostatic, surveillance profile supported by oxidative phosphorylation, to one in which glycolysis is impaired. Conversely, the control iPS-Mg responded to the pro-inflammatory stimuli in a similar manner to recent studies that have employed primary microglia cultures.…”

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia

“…Both responses require rapid energy production which is produced when microglia undergo the metabolic switch to glycolysis (Finucane et al, 2019;Jiang et al, 2016). Glycolysis allows energy production and uptake of essential nutrients to support the rapid changes required by "activated" microglia in response to a stimulus, such as phagocytosis, proliferation, migration and induction of protein synthesis for cytokine and chemokine secretion (Vander Heiden et al, 2009;Shen et al, 2017;Gu et al, 2017;Culmsee et al, 2018). Indeed, we identified the ability of the TREM2 variant expressing iPS-Mg to undergo a normal switch in metabolism from a homeostatic, surveillance profile supported by oxidative phosphorylation, to one in which glycolysis is impaired.…”

Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges

“…Mitochondria are intracellular organelles required for numerous cellular functions, including control of energy metabolism and regula-tion of ROS production, calcium homeostasis, and apoptosis. During the inflammatory process, released interleukins are capable of activating the KYN pathway, which generates catabolites, called TRYCATs that cause a high calcium influx inducing mitochondrial dysfunction along with an impairment in the cellular antioxidant system [119,120]. This becomes a cycle as the mitochondrial dysfunction and potential losses of the mitochondrial membrane lead to a rapid increase in the production of mitochondrial reactive oxygen species (MROS), which are also activators of the inflammasome (NLRP3) [121] ( Figure 2).…”