Mitochondrial antioxidants abate SARS-COV-2 pathology in mice.

Autor:	Guarnieri JW; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104., Lie T; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.; University of Pennsylvania, Philadelphia, PA 19104., Albrecht YES; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Hewin P; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Jurado KA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Widjaja GA; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104., Zhu Y; Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104., McManus MJ; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.; Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104., Kilbaugh TJ; Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104., Keith K; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104., Potluri P; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104., Taylor D; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104., Angelin A; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104., Murdock DG; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.; Division of Human Genetics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Wallace DC; The Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.; Division of Human Genetics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 23; Vol. 121 (30), pp. e2321972121. Date of Electronic Publication: 2024 Jul 15.
DOI:	10.1073/pnas.2321972121
Abstrakt:	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance. Competing Interests: Competing interests statement:D.C.W. is on the scientific advisory boards of Pano Therapeutics, Inc. and Medical Excellent Capital, and published a manuscript with S.E. Schriner in 2022.
Databáze:	MEDLINE
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