Mitofusin 2, a key coordinator between mitochondrial dynamics and innate immunity

Figures & data

Table 1. The role of MFN2 in innate immune responses during infection

Pathogen	Model	Effect	Mechanism	Ref.
Viral infection
EMCV, Measles, VSV	HEK 293T cells; MEFs	Inhibition of RLR-induced antiviral signaling	Interaction with carboxyl-terminal MAVS	[11]
Influenza virus A (H1N1)	A549 cells; Stress mice model	Inhibition of RLR-induced antiviral signaling	Interaction with and degradation of MAVS	[89]
EMCV, Influenza virus, Newcastle disease virus, SeV, Sindbis virus, VSV	HEK 293T cells; MEFs	No effects	ND for MFN2; MFN1 interacts with MAVS and activates type I IFN signaling	[90]
Cytomegalovirus	HeLa; HEK 293T cell	No effects	ND for MFN2; MFN1 interacts with MAVS and activates type I IFN signaling	[8]
Human immunodeficiency virus1	Human monocyte-derived macrophages	Increase in viral reservoir	Inhibition of BCL2L11-mediated MMP disruption by TREM1	[91]
Dengue virus	A549 cells	Attenuation of virus-induced cytopathic effects	Suppression of caspase 3 activation and MMP disruption	[92]
EMCV, SeV, VSV	HEK 293T cells; Mfn1 and Mfn2 double mutant MEFs	Induction of RLR-induced antiviral responses	Enhancement of adequate MMP and rearrangement of MAVS	[93]
EMCV, Influenza virus, Measles	BMDMs; HEK 293T cells; J774A.1 mouse macrophages	Activation of inflammasome	Interaction with NLRP3 and MAVS complex	[94]
Bacterial infection
ESAT-6, Mtb lysate	PBMCs; THP-1 cells	Activation of inflammasome	Interaction with NLRP3	[95]
Aeromonas hydrophila, Listeria monocytogenes, LPS, Mtb	BMDMs; Mfn2-cKO mice; L-929 cells; PMs	Induction of antibacterial responses and antigen processing	Increase in mitochondrial ROS and activation of ERK1/2, p38, and NF-κB	[12]
BCG, L. monocytogenes, Mtb,Mycobacteroides abscessus	BMDMs; Mfn2-cKO mice; PMs; RAW264.7 cells	Enhancement of aerobic glycolysis and xenophagy	Induction of mitochondrial ROS and HIF-1α	[14]
Mtb	BMDMs; RAW264.7 cells	Increase in bacterial growth	Inhibition of MMP disruption and apoptosis	[101]
Parasitic infection
Leishmania donovani	Golden hamsters; PMs from BALB/c mice; RAW264.7 cells	Enhancement of antiparasitic microRNAs	Destabilization and compartmentalization of miRNP by mitochondria-ER tethering	[13]

BCG, Mycobacterium bovis bacillus Calmette-Guérin; BCL2L11, B-cell lymphoma 2 like 11; BMDM, bone-marrow-derived macrophage; EMCV, encephalomyocarditis virus; ER, endoplasmic reticulum; ERK, extracellular signal-regulated protein kinase; ESAT-6, 6-kDa early secreted antigenic target; HIF-1α, hypoxia-inducible factor 1 alpha; IFN, interferon; LPS, lipopolysaccharide; MAVS, mitochondrial antiviral-signaling protein; MEF, mouse embryonic fibroblast; Mfn1, mitofusin 1; Mfn2, mitofusin2; Mfn2-cKO mice, Mfn2^fl/fl:LysM^c/c mice; miRNP, microribonucleoprotein; MMP, mitochondrial membrane potential; Mtb, Mycobacterium tuberculosis; ND, Not detected; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, nucleotide-binding and oligomerization domain-like receptor pyrin domain-containing protein 3; PBMC, peripheral blood mononuclear cell; PM, peritoneal macrophage; RLR, retinoic acid-inducible gene-I-like receptors; ROS, reactive oxygen species; SeV, Sendai virus; TREM1, triggering receptor expressed on myeloid cells 1; VSV, Vesicular stomatitis virus

Table 2. The role of MFN2 in controlling inflammation, fibrosis, and atherogenesis

Effects	Model	Mechanism	Ref
Inflammation
Inhibition of metabolic-induced inflammation	BMDMs from Mfn2-cKO mice	Enhancement of IL-12 secretion by ghrelin	[103]
Alleviation of blood-brain barrier breakdown	Cardiac ischemia/reperfusion injured rats	Increase in claudin5 by pretreatment of mitochondrial fusion promotor M1	[16]
Suppression of LPS-induced mitochondrial dynamic disequilibrium	Murine NR8383 macrophage cells	Restoration of MFN1, MFN2, and OPA1 by activation of PKC-α/HO-1 signaling	[104]
Relieving mitochondrial dysfunction in nonalcoholic fatty liver disease and sepsis	BLN.CL2 hepatocytes; Human liver tissue; Trem2^−/- mice	Decrease in a blockade MFN2 of miR-106b-5p through TREM2-mediated exosome	[105]
Fibrosis
Alleviation of liver fibrosis	AML12 hepatocytes; BMDMs; CCl4-induced liver fibrosis mice; HSC-T16 hepatic stellate cells	Suppression of TGF-β1/Smad signaling and collagen production	[106]
Protection from kidney fibrosis	Mfn2-cKO, PINK1^−/-, Prkn^−/- mice; BMDMs; Peritoneal macrophages; Renal macrophages	Enhancement of mitophagy through PINK1-mediated MFN2 phosphorylation and recruiting Parkin	[107]
Atherogenesis
Inhibition of intracellular lipid accumulation	ApoE^−/- mice; RAW264.7 and THP-1 cells	Induction of cholesterol transporters by PPARγ activation and inhibition of ERK1/2 and p38	[108]
Augmentation of mitophagy in oxidized LDL-exposed status	Apoa1bp^−/- mice; BMDMs; HEK 293T cells; Human carotid tissue	Ubiquitination of MFN2 through interaction between Parkin and N-terminal domain of AIBP	[17]

AIBP, apolipoprotein A-I binding protein (encoded by Apoa1bp gene); ApoE, apolipoprotein E; BMDM, bone marrow-derived macrophage; ERK1/2, extracellular signal-regulated protein kinase 1/2; HO-1, heme oxygenase-1; IL-12, interleukin 12; LDL, low-density lipoprotein; LPS, lipopolysaccharides; MFN2, mitofusin2; Mfn2-cKO mice, Mfn2^fl/fl:LysM^c/c conditional knock-out mice; OPA1, optic atrophy 1 (mitochondrial dynamin like GTPase); PINK1, phosphatase and tensin homolog-induced kinase 1; PKC-α, protein kinase C-alpha; PPARγ, peroxisome proliferator-activated receptor gamma; TGF-β1, transforming growth factor beta 1; TREM2, triggering receptor expressed on myeloid cells 2

Figure 1. A schematic model of MFN2 and its metabolic roles in macrophages during infection during mycobacterial infection, macrophage MFN2 functions in the enhancement of host defense through activation of inflammatory cytokine generation and xenophagy via interaction with LAMP1. MFN2-mediated innate immune activation depends on the generation of mitochondrial reactive oxygen species (ROS), which are mainly produced by mitochondrial respiratory chain complex I. mitochondrial ROS are required for the induction of HIF-1α that leads to the production of IL-1β for inflammatory signaling and gearing aerobic glycolysis up by LDHA. Additionally, MFN2 is crucial for the maintenance of mitochondrial Ca²⁺ homeostasis and mitochondrial membrane potential through tethering mitochondria and endoplasmic reticulum. HIF-1α, hypoxia-induced factor 1-α; IL-1β, interleukin 1 beta; LAMP1, lysosomal-associated membrane protein 1; LDHA, lactate dehydrogenase A; MFN2, mitofusion2

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Data Availability

Data sharing not applicable – no new data generated.