Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

Abstract

Lack of immune system cells or impairment in differentiation of immune cells is the basis for many chronic diseases. Metabolic changes could be the root cause for this immune cell impairment. These changes could be a result of altered transcription, cytokine production from surrounding cells, and changes in metabolic pathways. Immunity and mitochondria are interlinked with each other. An important feature of mitochondria is it can regulate activation, differentiation, and survival of immune cells. In addition, it can also release signals such as mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS) to regulate transcription of immune cells. From current literature, we found that mitochondria can regulate immunity in different ways. First, alterations in metabolic pathways (TCA cycle, oxidative phosphorylation, and FAO) and mitochondria induced transcriptional changes can lead to entirely different outcomes in immune cells. For example, M1 macrophages exhibit a broken TCA cycle and have a pro-inflammatory role. By contrast, M2 macrophages undergo β-oxidation to produce anti-inflammatory responses. In addition, amino acid metabolism, especially arginine, glutamine, serine, glycine, and tryptophan, is critical for T cell differentiation and macrophage polarization. Second, mitochondria can activate the inflammatory response. For instance, mitochondrial antiviral signaling and NLRP3 can be activated by mitochondria. Third, mitochondrial mass and mobility can be influenced by fission and fusion. Fission and fusion can influence immune functions. Finally, mitochondria are placed near the endoplasmic reticulum (ER) in immune cells. Therefore, mitochondria and ER junction signaling can also influence immune cell metabolism. Mitochondrial machinery such as metabolic pathways, amino acid metabolism, antioxidant systems, mitochondrial dynamics, mtDNA, mitophagy, and mtROS are crucial for immune functions. Here, we have demonstrated how mitochondria coordinate to alter immune responses and how changes in mitochondrial machinery contribute to alterations in immune responses. A better understanding of the molecular components of mitochondria is necessary. This can help in the development of safe and effective immune therapy or prevention of chronic diseases. In this review, we have presented an updated prospective of the mitochondrial machinery that drives various immune responses.

Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

“…Mitochondria regulate energy production through the coordination of fission (fragmentation of mitochondria) and fusion (elongation of mitochondria). Fused mitochondrial morphology supports higher levels of ATP generation via oxidative phosphorylation (Angajala et al, 2018). Fusion and fission is a dynamic process regulated by a number of proteins.…”

Monocyte-specific changes in gene expression implicateLACTB2andPLIN2in Alzheimer’s disease

“…Malfunction of mitochondrial processes implicated specifically in AD include oxidative damage (Nunomura et al, 2001) and accumulation of APP on mitochondrial membranes (Anandatheerthavarada et al, 2003). More recently it has been shown that mitochondria are important in immune cell regulation; influencing immune cell metabolism, differentiation, activation of the inflammatory response and regulating transcription (Angajala et al, 2018). Variants in mitochondrial DNA (mtDNA) have been associated with AD (Shoffner et al, 1993), but many of the processes that affect mitochondrial function, involve nuclear-encoded proteins (Ali et al, 2019), so it is more likely that variants in nuclear genes that affect mitochondrial function will affect AD pathology.…”

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

“…Next, we set to determine the cell intrinsic stimuli (DAMPs) that fuels the enduring IFNs signaling in Irgm1 -/mice. In the absence of external stimuli, the endogenous DAMPs from dysfunctional mitochondria are the major triggers for the type 1 IFN response (Angajala et al, 2018;West et al, 2015;Zhang et al, 2010). We and others have shown that depletion of IRGM in human cells or mice results in defective autophagy (Dong et al, 2015;He et al, 2012;Mehto et al, 2019) ( Supplementary Figure 5A and 5B) and this can result in impaired mitophagy and accumulation of defunct mitochondria.…”

“…This data is consistent with previous observations where overexpression of IRGM leads to mitochondrial fission and depolarization (Singh et al, 2010), and here we observed fused and hyperpolarized mitochondria in IRGM deficient cells. The hyperpolarized state of mitochondria is often associated with the production of mitochondrial reactive oxygen species (mtROS) leading to apoptosis or necrosis and also autoimmune diseases (Angajala et al, 2018;Chen et al, 2017;Galloway and Yoon, 2012;Gergely et al, 2002a;Gergely et al, 2002b;Perl et al, 2004). Indeed, the mitochondrial superoxide and cellular total ROS levels, as measured by MitoSOX™ and CellRox™ dyes, were elevated in IRGM-depleted THP-1 cells, mice BMDM's and human PBMC's ( Figure 5P, Supplementary figure 5G and 5H).…”