Overall, our findings demonstrate that MFN2 is a key coordinator of innate immune responses against intracellular bacterial infection through the maintenance of aerobic glycolysis and activation of xenophagy via HIF-1α. Furthermore, MFN2 interaction with the late-endosomal protein Rab7 contributed to activation of xenophagy during mycobacterial infection. In addition, MFN2 was required for the activation of xenophagy against Mycobacterium tuberculosis (Mtb) infection through HIF-1α. Here we report that MFN2 promoted macrophage inflammatory signaling through optimal induction of aerobic glycolysis via hypoxia-inducible factor (HIF)-1α, which is activated by mitochondrial respiratory chain complex I and ROS, triggered by bacterial infection. Because macrophages are critical to the functioning of the innate immune response, we investigated the mechanistic role of MFN2 in macrophages using Mfn2 f/f LysM Cre + ( Mfn2 CKO) mice and their littermate controls for innate host defense against mycobacterial and listerial infections. In addition, whether MFN2 is involved in the regulation of immunometabolism and xenophagy, both of which are critically related to innate defense 13, remains largely overlooked. Recently, MFN2 functions in macrophages have been reported in terms of inflammatory responses during bacterial infection and sepsis 12 however, the mechanisms by which MFN2 regulates innate host defense against intracellular bacterial infection remain to be characterized. Moreover, the association between MFN2 and NLRP3 is required for inflammasome activation in response to RNA viruses 11. MFN2 is also involved in cytoprotection, as it interacts with the NAD-dependent deacetylating enzyme sirtuin 1 (SIRT1), which deacetylates MFN2 8. MFN2 is required for controlling insulin signaling by modulating reactive oxygen species (ROS) and endoplasmic reticulum stress 9, 10. However, the protein functions involved in shaping mitochondrial morphology and how they are involved in modulating antimicrobial innate defenses remain largely unknown.Īmong mitochondrion-shaping proteins, MFN2 is a major mitochondrial fusion protein that coordinates mitochondrial quality control 7, 8. An imbalance in mitochondrial fusion and fission is associated with various pathological diseases like type 2 diabetes 4, Alzheimer’s disease 5, and heart failure 6. The mitofusin proteins 1 (MFN1), 2 (MFN2), and optic atrophy (Opa1) are involved in the processes of mitochondrial fusion, whereas dynamin-related protein 1 (Drp1) and mitochondrial fission 1 (Fis1) proteins participate in the mitochondrial fission processes 3.
The dynamic mitochondrial morphological changes are tightly controlled by dynamin-related GTPases, which constitute the core system of mitochondrial fusion and fission cycles 3. Morphological changes, i.e., mitochondrial fission and fusion, are critical for maintaining mitochondrial quality control through the removal of damaged mitochondria 2. Mitochondria are recognized as crucial hubs for the orchestration of a variety of physiological functions including cell survival, growth, death, and metabolic homeostasis 1. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. MFN2 did not impact mitophagy during infection however, it promoted xenophagy activation through HIF-1α. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection.
Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Mitochondrial function and innate immunity are intimately linked however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown.
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