TY - JOUR
T1 - Elevated serum mtDNA in COVID-19 patients is linked to SARS-CoV-2 envelope protein targeting mitochondrial VDAC1, inducing apoptosis and mtDNA release
AU - Shteinfer-Kuzmine, Anna
AU - Verma, Ankit
AU - Bornshten, Rut
AU - Ben Chetrit, Eli
AU - Ben-Ya’acov, Ami
AU - Pahima, Hadas
AU - Rubin, Ethan
AU - Mograbi, Yosef
AU - Shteyer, Eyal
AU - Shoshan-Barmatz, Varda
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12/1
Y1 - 2024/12/1
N2 - Mitochondria dysfunction is implicated in cell death, inflammation, and autoimmunity. During viral infections, some viruses employ different strategies to disrupt mitochondria-dependent apoptosis, while others, including SARS-CoV-2, induce host cell apoptosis to facilitate replication and immune system modulation. Given mitochondrial DNAs (mtDNA) role as a pro-inflammatory damage-associated molecular pattern in inflammatory diseases, we examined its levels in the serum of COVID-19 patients and found it to be high relative to levels in healthy donors. Furthermore, comparison of serum protein profiles between healthy individuals and SARS-CoV-2-infected patients revealed unique bands in the COVID-19 patients. Using mass spectroscopy, we identified over 15 proteins, whose levels in the serum of COVID-19 patients were 4- to 780-fold higher. As mtDNA release from the mitochondria is mediated by the oligomeric form of the mitochondrial-gatekeeper—the voltage-dependent anion-selective channel 1 (VDAC1)—we investigated whether SARS-CoV-2 protein alters VDAC1 expression. Among the three selected SARS-CoV-2 proteins, small envelope (E), nucleocapsid (N), and accessory 3b proteins, the E-protein induced VDAC1 overexpression, VDAC1 oligomerization, cell death, and mtDNA release. Additionally, this protein led to mitochondrial dysfunction, as evidenced by increased mitochondrial ROS production and cytosolic Ca2+ levels. These findings suggest that SARS-CoV-2 E-protein induces mitochondrial dysfunction, apoptosis, and mtDNA release via VDAC1 modulation. mtDNA that accumulates in the blood activates the cGAS-STING pathway, triggering inflammatory cytokine and chemokine expression that contribute to the cytokine storm and tissue damage seen in cases of severe COVID-19.
AB - Mitochondria dysfunction is implicated in cell death, inflammation, and autoimmunity. During viral infections, some viruses employ different strategies to disrupt mitochondria-dependent apoptosis, while others, including SARS-CoV-2, induce host cell apoptosis to facilitate replication and immune system modulation. Given mitochondrial DNAs (mtDNA) role as a pro-inflammatory damage-associated molecular pattern in inflammatory diseases, we examined its levels in the serum of COVID-19 patients and found it to be high relative to levels in healthy donors. Furthermore, comparison of serum protein profiles between healthy individuals and SARS-CoV-2-infected patients revealed unique bands in the COVID-19 patients. Using mass spectroscopy, we identified over 15 proteins, whose levels in the serum of COVID-19 patients were 4- to 780-fold higher. As mtDNA release from the mitochondria is mediated by the oligomeric form of the mitochondrial-gatekeeper—the voltage-dependent anion-selective channel 1 (VDAC1)—we investigated whether SARS-CoV-2 protein alters VDAC1 expression. Among the three selected SARS-CoV-2 proteins, small envelope (E), nucleocapsid (N), and accessory 3b proteins, the E-protein induced VDAC1 overexpression, VDAC1 oligomerization, cell death, and mtDNA release. Additionally, this protein led to mitochondrial dysfunction, as evidenced by increased mitochondrial ROS production and cytosolic Ca2+ levels. These findings suggest that SARS-CoV-2 E-protein induces mitochondrial dysfunction, apoptosis, and mtDNA release via VDAC1 modulation. mtDNA that accumulates in the blood activates the cGAS-STING pathway, triggering inflammatory cytokine and chemokine expression that contribute to the cytokine storm and tissue damage seen in cases of severe COVID-19.
KW - Apoptosis
KW - COVID-19
KW - Mitochondria
KW - VDAC1
KW - mtDNA
UR - http://www.scopus.com/inward/record.url?scp=85205919397&partnerID=8YFLogxK
U2 - 10.1007/s10495-024-02025-5
DO - 10.1007/s10495-024-02025-5
M3 - Article
C2 - 39375263
AN - SCOPUS:85205919397
SN - 1360-8185
VL - 29
SP - 2025
EP - 2046
JO - Apoptosis
JF - Apoptosis
IS - 11-12
ER -