SARS-CoV-2 membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK

Abstract

Deaths caused by coronavirus disease 2019 (COVID-19) are largely due to the lungs edema resulting from the disruption of the lung alveolo-capillary barrier, induced by SARS-CoV-2-triggered pulmonary cell apoptosis. However, the molecular mechanism underlying the proapoptotic role of SARS-CoV-2 is still unclear. Here, we revealed that SARS-CoV-2 membrane (M) protein could induce lung epithelial cells mitochondrial apoptosis. Notably, M protein stabilized B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) via inhibiting its ubiquitination and promoted BOK mitochondria translocation. The endodomain of M protein was required for its interaction with BOK. Knockout of BOK by CRISPR/Cas9 increased cellular resistance to M protein-induced apoptosis. BOK was rescued in the BOK-knockout cells, which led to apoptosis induced by M protein. M protein induced BOK to trigger apoptosis in the absence of BAX and BAK. Furthermore, the BH2 domain of BOK was required for interaction with M protein and proapoptosis. In vivo M protein recombinant lentivirus infection induced caspase-associated apoptosis and increased alveolar-capillary permeability in the mouse lungs. BOK knockdown improved the lung edema due to lentivirus-M protein infection. Overall, M protein activated the BOK-dependent apoptotic pathway and thus exacerbated SARS-CoV-2 associated lung injury in vivo. These findings proposed a proapoptotic role for M protein in SARS-CoV-2 pathogenesis, which may provide potential targets for COVID-19 treatments.

SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia

“…Since apoptosis is a surrogate for cell death and lung injury, our findings are also consistent with the observation that elevated levels of circulating mitochondrial DNA in COVID-19 pneumonia patients predict poor outcomes [ 47 ]. In 2022, Yang et al showed that transduction of AEC with SARS-CoV-2 M protein induced mitochondrial apoptosis [ 48 ] by inhibiting the ubiquitination of B-cell lymphoma 2 (BCL-2)-related ovarian killer (BOK), thereby stabilizing BOK, and promoting mitochondrial translocation. Our findings support their conclusions and we extend their work by demonstrating the proapoptotic effects of coronavirus infections using replicating SARS-CoV-2 and identifying a conserved role for AIF in this apoptotic pathway.…”

Visualization of BOK pores independent of BAX and BAK reveals a similar mechanism with differing regulation

“…According to this model, BOK-mediated apoptosis would be regulated by its mitochondrial accumulation, for example via upregulation via proteosomal degradation as reported by Llambi et al in [13], or by alternative mechanisms controlling BOK localization that remain to be explored. A recent study reported that BOK levels were upregulated by the SARS-CoV-2 membrane protein (M), leading to apoptosis and lung edema in mice [47], which may open opportunities for BOK targeted interventions against COVID-19.…”

COVID‐19 and neurodegeneration: The mitochondrial connection

“…For example, in HEK293 cells, it has been shown that SARS‐CoV‐2 increases apoptosis via the interaction of protein ORF7a of the virus with the Bcl‐X L protein, a well‐known anti‐apoptotic protein (Tan et al, 2007). Further, in the case of the pulmonary edema which is found in some COVID‐19 patients, the viral M protein interacted with the Bcl‐2 and ovarian killer protein (BOK, a non‐canonical pro‐apoptotic member of the Bcl‐2 family) (Yang et al, 2022), mediating apoptosis. Other research groups have shown the importance of the ORF3a protein on the activation of apoptosis in several mammalian cell lines (Ren et al, 2020).…”

“…Further, in the case of the pulmonary edema which is found in some COVID-19 patients, the viral M protein interacted with the Bcl-2 and ovarian killer protein (BOK, a non-canonical pro-apoptotic member of the Bcl-2 family) (Yang et al, 2022), mediating apoptosis. Other research groups have shown the importance of the ORF3a protein on the activation of apoptosis in several mammalian cell lines (Ren et al, 2020).…”