bims-mikwok 2023-04-16 papers

Issue of 2023–04–16
five papers selected by
Avinash N. Mukkala, University of Toronto

FEBS J. 2023 Apr 15.

Rab26 promotes macrophage phagocytosis through regulation of MFN2 trafficking to mitochondria.

Di Wu, Yao Wang, Junxian Hu, Yuhang Xu, Daohui Gong, Pengfei Wu, Junkang Dong, Binfeng He, Hang Qian, Guansong Wang.

Acute respiratory distress syndrome (ARDS) is an inflammatory disorder of the lungs caused by bacterial or viral infection. Timely phagocytosis and clearance of pathogens by macrophages are important in controlling inflammation and alleviating ARDS. However, the precise mechanism of macrophage phagocytosis remains to be explored. Here, we show that the expression of Rab26 is increased in E. coli or Pseudomonas aeruginosa (Pa)-stimulated bone marrow-derived macrophages (BMDM). Knocking out Rab26 reduced phagocytosis and bacterial clearance by macrophages. Rab26 interacts with mitochondrial fusion protein mitofusin-2 (MFN2) and affects mitochondrial ROS (mtROS) generation by regulating MFN2 transport. The levels of MFN2 in mitochondria were reduced in Rab26-deficient BMDMs, and the levels of mtROS and ATP were significantly decreased. Knocking down MFN2 using siRNA resulted in decreased phagocytosis and killing ability of macrophages. Rab26 knockout reduced phagocytosis and bacterial clearance by macrophages in vivo, significantly increased inflammatory factors, aggravated lung tissue damage, and increased mortality in mice. Our results demonstrate that Rab26 regulates phagocytosis and clearance of bacteria by mediating the transport of MFN2 to mitochondria in macrophages, thus alleviating ARDS in mice and potentially in humans.

Keywords: Bacteria; MFN2; Macrophage; Phagocytosis; ROS; Rab26

DOI: https://doi.org/10.1111/febs.16793

Nat Commun. 2023 Apr 14. 14(1): 2132

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death.

Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.

DOI: https://doi.org/10.1038/s41467-023-37652-0

Int Immunopharmacol. 2023 Apr 10. pii: S1567-5769(23)00381-8. [Epub ahead of print]119 110060

Hepatocyte-derived extracellular vesicles miR-122-5p promotes hepatic ischemia reperfusion injury by regulating Kupffer cell polarization.

Long Liu, Fei Xiao, Jie Sun, Qi Wang, Aidong Wang, Fabiao Zhang, Zhu Li, Xuequan Wang, Zheping Fang, Yingli Qiao.

Ischemia reperfusion injury remains a major barrier to liver transplantation, especially using grafts from donation after circulatory death, and it is also a pressing issue to be solved in clinical practice. Kupffer cell polarization toward a proinflammatory M1 phenotype is an early trigger of liver ischemia-reperfusion injury. However, the molecular mechanism regulating Kupffer cell polarization has not yet been fully elucidated. We induced liver ischemia reperfusion injury in mice and obtained samples from patients undergoing liver transplantation, serum and hepatocytes-derived extracellular vesicles were isolated by differential ultracentrifugation. Kupffer cell polarization was examined by flow cytometry and immunofluorescence histochemistry. RNA-seq was conducted to detect the differentially expressed miRNAs in extracellular vesicles. The role and mechanism of exosomal miR-122-5p in liver ischemia-reperfusion injury were determined both in vitro and in vivo. We identified ischemia reperfusion induced extracellular vesicles as a major cause of hepatic inflammation and tissue damage using adoptive transfer and release inhibition. The study also demonstrated that hepatocyte-derived exosomal miR-122-5p mediates liver ischemia reperfusion injury by polarizing Kupffer cell via PPARδ down-regulation and NF-κB pathway activation using profiling and functional analysis. Moreover, inhibiting miR-122-5p with antagomir suppressed Kupffer cell M1 polarization and attenuated liver ischemia reperfusion injury. Overall, our study demonstrated that hepatocyte-derived exosomal miR-122-5p played a critical role in promoting hepatic ischemia reperfusion injury through modulating PPARδ signaling and NF-κB pathway to introduce M1 polarization of Kupffer cell. Inhibition of miR-122-5p exhibited a protective effect against liver ischemia reperfusion injury, suggesting a potential therapeutic target for liver transplantation.

Keywords: Extracellular vesicles; Ischemia reperfusion injury; Macrophage polarization; NF-κB; PPARδ; miRNA

DOI: https://doi.org/10.1016/j.intimp.2023.110060

Hepatol Int. 2023 Apr 12.

Therapeutic role of FNDC5/irisin in attenuating liver fibrosis via inhibiting release of hepatic stellate cell-derived exosomes.

Xin Liao, Yilin Luo, Fang Gu, Wen Song, Xin Nie, Qin Yang.

OBJECTIVE: Cleavage of fibronectin type III domain-containing protein 5 (FNDC5), a membrane-bound precursor protein, would cleave into a myokine, irisin, which is also expressed in the liver. FNDC5/Irisin has been reported to play a critical role in maintaining glucose and lipid homeostasis in the liver and in combating liver fibrosis. Recently, several studies have shown that extracellular vesicles (EVs) derived from hepatic stellate cells (HSCs) could modulate liver fibrosis; however, there is a large gap in understanding whether inhibition of fibrogenic EVs derived from HSCs could alleviate the progression of liver fibrosis. Here, we investigated the role of FNDC5/irisin in liver fibrosis and the mechanism of its inhibitory role in the release of HSC-derived fibrogenic EVs.
METHODS: Experiments were performed in wild-type and FNDC5-/- mice, primary mouse HSCs, and human hepatic stellate cell line (LX2). Mice were treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL) to induce liver fibrosis. EVs derived from HSCs were purified and injected intraperitoneally into mice.
RESULTS: Our results showed that FNDC5 deficiency exacerbated CCl4-induced liver fibrosis and activation of HSCs in mice. Moreover, fibrogenic EVs derived from PDGF-BB-treated HSCs promoted HSC migration in vitro and liver fibrosis in vivo. However, administration of irisin, a cleavage of FNDC5, inhibited the release of fibrogenic EVs and activation of HSCs by promoting ubiquitylation degradation of Rab27b. In vivo, the promoting role of HSC-derived fibrogenic EVs in liver fibrosis was also reversed by irisin.
CONCLUSION: All these results demonstrate that FNDC5/irisin is a novel therapeutic agent for chronic liver fibrosis.

Keywords: Extracellular vesicles; FNDC5; Hepatic stellate cells; Irisin; Liver fibrosis

DOI: https://doi.org/10.1007/s12072-023-10523-y

Dev Cell. 2023 Apr 10. pii: S1534-5807(23)00098-9. [Epub ahead of print]58(7): 597-615.e10

Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.

Ji Geng, Tejinder Pal Khaket, Jie Pan, Wen Li, Yan Zhang, Yong Ping, Maria Inmaculada Cobos Sillero, Bingwei Lu.

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.

Keywords: ER-mitochondria contact site; ERMCS; FMRP; FXS; VDAC; fragile X messenger ribonucleoprotein; fragile X syndrome; mito-Ca(2+) homeostasis; mitochondrial calcium homeostasis; voltage-dependent anion channel

DOI: https://doi.org/10.1016/j.devcel.2023.03.002