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Published on: January 7, 2013
SARS-CoV-2 ORF7a drives mitochondrial dysfunction via PDK4 activation and complex I inhibition
Raúl Fernández-Rodríguez1, Carmen M Soto-Jiménez1, Rebeca Acín-Pérez2
1Department of Genetics, Immunogenomics and Molecular Pathogenesis Group, UIC Zoonoses and Emergent Diseases ENZOEM, University of Córdoba (UCO), Córdoba, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain.
Cell Reports
|July 28, 2026
Summary
The SARS-CoV-2 accessory protein ORF7a disrupts host cell metabolism. It impairs mitochondrial function by affecting glucose and lipid pathways, highlighting a new target for therapeutic intervention.
Area of Science:
- Cell Biology
- Virology
- Metabolomics
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters host cell metabolism to promote viral replication and immune evasion.
- The specific roles of SARS-CoV-2 accessory proteins, like ORF7a, in this metabolic reprogramming are not well understood.
Purpose of the Study:
- To investigate the metabolic consequences of the SARS-CoV-2 accessory protein ORF7a.
- To elucidate the mechanisms by which ORF7a affects cellular metabolism, particularly mitochondrial function.
Main Methods:
- Lentiviral expression of ORF7a in human lung epithelial (A549) and monocytic (THP1) cells.
- Integrated transcriptomic, proteomic, and metabolomic analyses.
- High-resolution respirometry and Blue Native-PAGE to assess mitochondrial respiratory chain function.
Main Results:
- ORF7a significantly dysregulated glucose and lipid metabolism.
- Impaired mitochondrial oxidative phosphorylation, reduced respiration, increased reactive oxygen species, and mitochondrial depolarization were observed.
- ORF7a upregulated pyruvate dehydrogenase kinase 4 (PDK4), inhibiting pyruvate oxidation, and caused complex I dysfunction and defective respiratory supercomplex assembly.
Conclusions:
- SARS-CoV-2 ORF7a protein disrupts mitochondrial metabolism through both enzymatic regulation (PDK4) and direct destabilization of the respiratory chain.
- Mitochondria are a key target of SARS-CoV-2-induced metabolic reprogramming, offering potential therapeutic avenues.
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