Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/608091

Mitofusin 2 regulates neutrophil adhesive migration via suppressing Rac activation

Zhou, W.·Hsu, A. Y.·Wang, T.·Jeffries, J.·Mohammad, H. T.·Wang, X.·Umulis, D. M.·Seleem, M. N.·Deng, Q.
View original source ↗Export metadata ↓

Abstract

Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (Mfn2) regulates neutrophil homeostasis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue and trapped in the vasculature in zebrafish embryos. Human neutrophil-like cells deficient with MFN2 fail to arrest on activated endothelium under sheer stress or perform chemotaxis. Deletion of Mfn2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mfn2, but not Mfn1, -null mouse embryonic fibroblast cells have altered actin structure and are impaired in wound closure. MFN2-deficient neutrophil-like cells display heightened intracellular calcium levels and Rac activation after chemokine stimulation. Mechanistically, MFN2 maintains mitochondria-ER interaction. Restoring mitochondria-ER tether rescues the chemotaxis defect and Rac activation resulted from MFN2 depletion. Finally, inhibition of Rac restores chemotaxis in MFN2-deficient neutrophils. Altogether, we identified that MFN2 regulates neutrophil migration via suppressing Rac activation and uncovered a previously unrecognized role of MFN2 in regulating the actin cytoskeleton.

Source connections

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zhou, W., Hsu, A. Y., Wang, T., Jeffries, J., Mohammad, H. T., Wang, X., Umulis, D. M., Seleem, M. N., Deng, Q.. 2019-04-13. Mitofusin 2 regulates neutrophil adhesive migration via suppressing Rac activation. https://doi.org/10.1101/608091

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Endothelial Cell Specific Thioredoxin 1-Dependent Signaling in Oxygen-1 Induced Retinopathy

Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness, characterized byoxidative stress and dysregulated angiogenesis in preterm infants with immature antioxidant systems.This study aimed to investigate the specific role of endothelial cell-specific thioredoxin 1 (TXN1), a crucial oxidoreductase, in oxygen-induced retinopathy, hypothesizing that the absence of endothelial TXN1 directly impairs angiogenesis and exacerbates hyperoxia-induced injury. Methods: We generated tamoxifen-inducible, endothelial cell-specific Txn1 knockout mice (Txn1-iECKO) and utilized the oxygen-induced retinopathy (OIR) model, exposing litters to 85% oxygen from postnatal day 7 (P7) to P12. Retinal vascular morphology during vaso-obliteration and neovascularization phases, endothelial cell proliferation, and apoptotic cell death were assessed. Furthermore, human retinal microvascular endothelial cells (HRMECs) with TXN1 knockdown were subjected to hyperoxic conditions, followed by comprehensive gene expression profiling using RT2 Profiler PCR arrays and Ingenuity Pathway Analysis. Results: Deletion of endothelial Txn1 significantly enhanced vascular regression during the hyperoxic vaso-obliteration phase at P12 and markedly exacerbated pathological neovascularization at P17. Txn1-deficient retinas exhibited significantly impaired endothelial cell proliferation during the vaso-obliteration phase, while apoptotic cell death remained unchanged. Transcriptomic analysis of TXN1-deficient HRMECs under hyperoxia revealed an enhanced activation of NRF2-mediated oxidative stress response pathways. Conclusions: These findings identify endothelial TXN1 as an essential and oxygen-dependent regulator of vascular development in ischemic retinopathy, primarily influencing endothelial proliferation and redox signaling. This suggests TXN1's crucial protective role and highlights its therapeutic potential to mitigate ROP progression by modulating endothelial cell responses to oxidative stress.

cell biology↗
bioRxiv2026

A Dynamic Stem Cell State Links Environmental Cues to Skeletal and Regenerative Fates

Stem cells faithfully generate tissue architecture during development, yet how their identity and regenerative output are reshaped as anatomical niches mature and environmental signals change with aging and injury remains poorly understood. Rare skeletal stem cells (SSCs) across diverse skeletal sites are defined by combinations of cell-surface markers, precluding their genetic interrogation in vivo. Here, using spatially informed single cell transcriptomics, we identify Pannexin-3 (Panx3) to mark a dynamic functional state within bona fide SSCs and establish Panx3-CreERT2 mice for its longitudinal interrogation. Panx3 SSCs exhibit long-term clonal persistence, self-renewal and multipotency, whereas Panx3- SSCs can acquire this state. Successive SSC cohorts engage the Panx3 state during skeletal development, osteoanabolic stimulation expands pre-existing Panx3 SSC clones and injury induces it locally in previously unlabeled progenitors. Thus, anatomically distinct progenitors can converge on a common stem cell state in response to different environmental inputs. Three-dimensional reconstruction of chondrogenic niches further identifies signals that redirect Panx3-lineage cells towards stable cartilage, enabling durable regeneration in aged and osteoarthritic joints and with human SSCs. These findings establish anatomical origin, stem cell state and lineage fate as separable dimensions of stem cell identity and provide genetic access for interrogating and directing endogenous SSC function.

cell biology↗
bioRxiv2026

Proteome-wide profiling reveals compartment-specific RNA buffering of protein aggregation during stress

Cellular adaptation to stress requires extensive remodeling of RNA metabolism. The rewiring of the RNA-protein interaction landscape and the assembly of biomolecular condensates are central to this response, yet the global stress-induced reorganization of macromolecular RNA-protein assemblies remains incompletely characterized. Here, we apply R-DeeP, a density gradient approach coupled to quantitative mass spectrometry, to profile the RNA-dependent sedimentation behaviour of the Saccha-romyces cerevisiae proteome during heat and salt stress. We demonstrate that stress triggers a profound, stress-specific reorganization of the RNA interactome. Many proteins undergo pronounced, selective shifts into high-molecular weight fractions, indicative of aggregation. RNase treatment markedly exacerbates this aggregation, consistent with the model that RNA acts as a general chaperone that keeps proteins with intrinsically disordered regions soluble. Strikingly, our data demonstrate that this protection is compartmentalised. Nuclear proteins are partially shielded from stress-induced aggregation. This protection coincides with the nuclear accumulation of RNA caused by a block of RNA export during stress, and RNase treatment abolishes this protection. Nuclear RNA retention may therefore act as a buffer that actively increases the local chaperoning capacity of the nucleus. In contrast, cytoplasmic proteins, including translation factors and ribonucleoprotein granule components, exhibit increased aggregation under stress. Fluorescence microscopy confirmed that increased biochemical aggregation in density gradients reflects changes in assembly state in vivo. For many stress-induced aggregators, these changes are visible as spatial reorganisation in stressed cells, such as the formation of foci. Our findings suggest that cells use subcellular RNA distribution to tune the condensation and/or aggregation threshold of proteins in a compartment-specific manner.

cell biology↗