Abstract
Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. 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. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. 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. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. 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.
Highlights
Mitochondrial function and innate immunity are intimately linked; the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown
We found that basal respiration and ATP production were significantly higher in Mfn[2] WT peritoneal macrophages (PMs) than in Mfn[2] CKO PMs after Mycobacterium tuberculosis (Mtb) infection (Fig. 4a, b)
We found that Mtb infection robustly upregulated co-localization between mitochondrial outer membrane protein TOM20 and lysosomal protein LAMP1 in Mfn[2] WT bone marrow-derived macrophages (BMDMs), and that this upregulation was significantly inhibited in Mfn[2] CKO BMDMs (Supplementary Fig. 8a, b)
Summary
Mitochondrial function and innate immunity are intimately linked; the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. ELISA analysis showed that TNF and IL-6 production was significantly inhibited in BMDMs from Mfn[2] CKO mice after Mtb or LM infection (Fig. 2c, d). The results showed that the phosphorylation level of NF-κB p65 was lower in BMDMs (Fig. 2f, g) and PMs (Supplementary Fig. 2e) from Mfn[2] CKO mice compared to macrophages from Mfn[2] WT mice during Mtb infection.
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