Biology subjects

Wollheim, C. B.

Publications and source records attributed to Wollheim, C. B..

3 recordsLinked to original sources

bioRxiv2025

Shedding of mitochondrial Voltage-Dependent Anion Channel-1 (VDAC1) Reflects COVID-19 Severity and Reveals Macrophage Dysfunction

COVID-19 severity correlates with lymphopenia and increased pro-inflammatory cytokines. However, the dysfunction of tissue macrophages in COVID-19 patients during the inflammatory cytokine storm has not been fully elucidated. Hospitalized COVID-19 patients were divided into three groups based on their symptomatic severity: exhibiting mild, moderate, or severe symptoms. Patients exhibited successively increased serum levels of mitochondrial voltage-dependent anion channel 1 (VDAC1) at days 0, 3, 7, 10, and 14, returning to those of non-infected subjects at day 28. Serum level of VDAC1 was positively correlated with COVID-19 severity and with increased white blood cell (WBC), neutrophil, lymphocyte, procalcitonin (PCT), and gamma-glutamyltransferase (GT) levels. Peripheral blood mononuclear cells (PBMCs) from hospitalized COVID-19 patients showed increased VDAC1 content concomitant with a reduced ATP content. Culture of monocytes, isolated from healthy individuals, and differentiated into polarized M1 macrophages, together with a cytokine mixture (IL-1{beta}, IFN-{gamma}, and TNF-), to mimic the inflammatory cytokine storm, for 24 h markedly increased VDAC1 and Monocyte chemoattractant protein-1 (MCP-1) release in culture medium. The presence of the cytokine mixture reduced the ATP content, cell viability, and the phagocytic capability of macrophages. Co-staining of VDAC1 and the plasma membrane marker Na+/K+-ATPase showed that cytokine-treatment mistargeted VDAC1 to the cell surface of macrophages. All these effects were prevented by VDAC1 inhibition using VBIT-4, VDAC1-specific antibody (VDAC1-ab), or metformin. Our findings indicate that increased VDAC1 expression and cell surface mistargeting in immune cells might be associated with cell dysfunction, potentially contributing to the severity of COVID-19 infection. The data also indicate serum VDAC1 as a biomarker of COVID-19 severity and the use of VDAC1 inhibitors as potential drug candidates restoring macrophages and PBMCs function in individuals severely affected by COVID-19.

pathology↗

bioRxiv2025

Harnessing distinct tissue-resident immune niches via S100A9/TLR4 improves ketone, lipid, and glucose metabolism

Immunometabolism contributes to the development of metabolic diseases. Yet, how certain metabolic disorders, such as insulin deficiency (ID), influence immune cell function is poorly understood. Here, we observe that ID rearranges the immune landscape of the liver, causing a decrease in T cells and an increase in Kupffer cells, accompanied by a shift in the transcriptome and polarization of the latter. Treating ID mice with the protein S100A9 rescues the polarization and lipid-related changes caused by ID in the KCs, and rescues hypertriglyceridemia and hyperketonemia in a TLR4-dependent manner. Additionally, S100A9 acts on other immune niches to increase glucose uptake in skeletal muscle, improving hyperglycemia. In summary, the S100A9-TLR4 axis is a new tool to harness immune cells for improving ID-related metabolic dysfunction.

physiology↗

bioRxiv2025

Perilysosomal Ca2+ overload impairs autophagic degradation in β-cell lipotoxicity

Saturated fatty acids impose lipotoxic stress on pancreatic {beta}-cells, leading to {beta}-cell failure and diabetes. In this study, we investigate the critical role of organellar Ca2+ disturbance on defective autophagy and {beta}-cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca2+ elevation, sustained mTORC1 activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in {beta}-cells. These Ca2+ aberrations with autophagy defects by palmitate were prevented by a mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca2+ overload, strategies such as lowering extracellular Ca2+, employing voltage-gated Ca2+ channel blocker or ATP-sensitive K+ channel opener effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca2+ into the endoplasmic reticulum (ER) with an ER Ca2+ ATPase activator, restores TRPML1 activity, promotes autophagic flux, and improves survival of {beta}-cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress-Ca2+ overload-mTORC1 pathway involves in TRPML1 suppression and defective autophagy during {beta}-cell lipotoxicity. Restoring perilysosomal Ca2+ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.

physiology↗