Shedding of mitochondrial Voltage-Dependent Anion Channel-1 (VDAC1) Reflects COVID-19 Severity and Reveals Macrophage Dysfunction
Marie Sjögren, Pontus Dunér, Yang De Marinis, Ariane Neumann, Karin Leandersson, Magnus Rasmussen, Claes B Wollheim, Albert Salehi
doi:10.1101/2025.07.07.663218
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-1β, IFN-γ, and TNF-α), 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. .
Author contributions M.S. conceived and designed the experiments. M.S., A.S., and C.B.W. supervised the project. M.S., P.D., and A.S. performed the experiments and analysed the data. K.L. was involved as an immunologist and macrophage expert. M.R. collected the clinical samples, and A.N. purified the PBMC. M.S. and A.S. wrote the first draft of the manuscript, which was substantially revised by C.B.W. All co-authors proofread the manuscript and provided valuable suggestions. All clinical parameters are the median of the highest value for each patient (except for lymphocytes and platelets),
Declaration of Interests
Tables and Figures
Study where the lowest value for each patient is given. Group 1: Mild disease -No oxygen, Group 2: Moderate disease -1-6 L of oxygen/ minute, Group 3: Severe disease -More than 6 L of oxygen per minute.
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>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.</jats:p>\n <jats:p>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.</jats:p>\n <jats:p>Culture of monocytes, isolated from healthy individuals, and differentiated into polarized M1 macrophages, together with a cytokine mixture (IL-1β, IFN-γ, and TNF-α), 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<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup>-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.</jats:p>\n <jats:p>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.</jats:p>\n <jats:p>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.</jats:p>",
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