Mitochondrial dynamics in macrophages: divide to conquer or unite to survive?

Abstract

Mitochondria have long been appreciated as the metabolic hub of cells. Emerging evidence also posits these organelles as hubs for innate immune signalling and activation, particularly in macrophages. Macrophages are front-line cellular defenders against endogenous and exogenous threats in mammals. These cells use an array of receptors and downstream signalling molecules to respond to a diverse range of stimuli, with mitochondrial biology implicated in many of these responses. Mitochondria have the capacity to both divide through mitochondrial fission and coalesce through mitochondrial fusion. Mitochondrial dynamics, the balance between fission and fusion, regulate many cellular functions, including innate immune pathways in macrophages. In these cells, mitochondrial fission has primarily been associated with pro-inflammatory responses and metabolic adaptation, so can be considered as a combative strategy utilised by immune cells. In contrast, mitochondrial fusion has a more protective role in limiting cell death under conditions of nutrient starvation. Hence, fusion can be viewed as a cellular survival strategy. Here we broadly review the role of mitochondria in macrophage functions, with a focus on how regulated mitochondrial dynamics control different functional responses in these cells.

Proteome profiling identifies a link between the mitochondrial pathways and host-microbial sensor ELMO1 followingSalmonellainfection

“…Mitochondrial fission has primarily been associated with proinflammatory responses and metabolic adaptation, so it can be considered combative strategy immune cells utilize. In contrast, mitochondrial fusion has a more protective role in limiting cell death under conditions of nutrient starvation (57). Alterations in mitochondrial dynamics are associated with cancer development, and progression of cardiovascular and neurodegenerative conditions (58)(59)(60)(61).…”

Dynamic changes in mitochondria support phenotypic flexibility of microglia

“…Mitochondria can alter their distribution within the cell, as well as undergo fission and fusion (52,82). Work in peripheral macrophages demonstrates that such mitochondrial structural remodeling can regulate key cellular functions (34–39). We found that microglial mitochondria exhibit most of the same forms of dynamic remodeling described in other cell types.…”

“…For example, in neurons, mitochondria can regulate emergence of synaptic plasticity (45,75) and, in astrocytes, mitochondria can regulate morphological and functional maturation of the cell (75,77). Mitochondria can also regulate the inflammatory state of macrophages and capacity of these cells to rapidly adjust their cellular phenotype in response to various challenges (34)(35)(36)(37)(38)(39)76). Given evidence that mitochondrial dysfunction is implicated in developmental delays, epilepsy, migraine, psychiatric disorders, aging, and risk for neurodegeneration (78,79), a better understanding of how mitochondria impact the function of specific CNS cell types should be a priority for the field.…”

“…Microglia respond to this challenge with prominent changes in gene expression that emerge within hours of LPS injection and changes in morphology and further changes in gene expression that emerge by 24-48 hours post-injection (59). In vitro studies indicate that mitochondrial structure and functional state are altered within microglia following LPS exposure (60)(61)(62)(63) and, in macrophages, mitochondrial alterations play an essential role in enabling and regulating changes in macrophage attributes as they respond to inflammatory challenges (34)(35)(36)(37)(38)(39)64,65).…”

“…Mitochondria influence intracellular signaling by buffering calcium, by providing metabolites needed for protein post-translational modifications, by interacting physically with other organelles, and by signaling to the nucleus to impact gene expression (29)(30)(31)(32). Research in macrophages supports this view of mitochondria as signaling hubs, demonstrating that mitochondria regulate macrophage responses to pathology and shifts into distinct inflammatory states (33)(34)(35)(36)(37)(38)(39). Little is known about mitochondria in microglia in vivo.…”