TY - JOUR
T1 - Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts
AU - Guarnieri, Joseph W.
AU - Dybas, Joseph M.
AU - Fazelinia, Hossein
AU - Kim, Man S.
AU - Frere, Justin
AU - Zhang, Yuanchao
AU - Albrecht, Yentli Soto
AU - Murdock, Deborah G.
AU - Angelin, Alessia
AU - Singh, Larry N.
AU - Weiss, Scott L.
AU - Best, Sonja M.
AU - Lott, Marie T.
AU - Zhang, Shiping
AU - Cope, Henry
AU - Zaksas, Victoria
AU - Saravia-Butler, Amanda
AU - Meydan, Cem
AU - Foox, Jonathan
AU - Mozsary, Christopher
AU - Bram, Yaron
AU - Kidane, Yared
AU - Priebe, Waldemar
AU - Emmett, Mark R.
AU - Meller, Robert
AU - Demharter, Sam
AU - Stentoft-Hansen, Valdemar
AU - Salvatore, Marco
AU - Galeano, Diego
AU - Enguita, Francisco J.
AU - Grabham, Peter
AU - Trovao, Nidia S.
AU - Singh, Urminder
AU - Haltom, Jeffrey
AU - Heise, Mark T.
AU - Moorman, Nathaniel J.
AU - Baxter, Victoria K.
AU - Madden, Emily A.
AU - Taft-Benz, Sharon A.
AU - Anderson, Elizabeth J.
AU - Sanders, Wes A.
AU - Dickmander, Rebekah J.
AU - Baylin, Stephen B.
AU - Wurtele, Eve Syrkin
AU - Moraes-Vieira, Pedro M.
AU - Taylor, Deanne
AU - Mason, Christopher E.
AU - Schisler, Jonathan C.
AU - Schwartz, Robert E.
AU - Beheshti, Afshin
AU - Wallace, Douglas C.
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023
Y1 - 2023
N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)–encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.
AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)–encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.
UR - http://www.scopus.com/inward/record.url?scp=85167531710&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85167531710&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abq1533
DO - 10.1126/scitranslmed.abq1533
M3 - Article
C2 - 37556555
AN - SCOPUS:85167531710
SN - 1946-6234
VL - 15
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 708
M1 - eabq1533
ER -