tetano
Editor, Senior Moderator
Cell Rep
. 2026 Jul 28;45(8):117755.
doi: 10.1016/j.celrep.2026.117755. Online ahead of print.
SARS-CoV-2 ORF7a drives mitochondrial dysfunction via PDK4 activation and complex I inhibition
Raúl Fernández-Rodríguez[SUP] 1 [/SUP], Carmen M Soto-Jiménez[SUP] 1 [/SUP], Rebeca Acín-Pérez[SUP] 2 [/SUP], Ana de Lucas-Rius[SUP] 3 [/SUP], Miguel Padilla-Blanco[SUP] 3 [/SUP], Luz M Sánchez-Mendoza[SUP] 4 [/SUP], Blanca D López-Ayllón[SUP] 5 [/SUP], Ángela Peralbo-Molina[SUP] 6 [/SUP], Eduardo Chicano-Gálvez[SUP] 6 [/SUP], José M Villalba[SUP] 7 [/SUP], José A Enríquez[SUP] 2 [/SUP], María Montoya[SUP] 3 [/SUP], Juan J Garrido[SUP] 1 [/SUP], Tránsito García-García[SUP] 8 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection reprograms host metabolism to favor viral replication and immune evasion, yet the contribution of accessory proteins remains poorly defined. Here, we characterize the metabolic effects of the SARS-CoV-2 accessory protein ORF7a. Lentiviral expression of ORF7a in human lung epithelial (A549) and monocytic (THP1) cells, combined with integrated transcriptomic, proteomic, and metabolomic analyses, revealed marked dysregulation of glucose and lipid metabolism. ORF7a impaired mitochondrial oxidative phosphorylation, reducing basal and maximal respiration, inducing mitochondrial depolarization, and increasing reactive oxygen species. Mechanistically, ORF7a upregulated pyruvate dehydrogenase kinase 4 (PDK4), enhancing phosphorylation of the pyruvate dehydrogenase complex and suppressing pyruvate oxidation. However, pharmacological PDK4 inhibition failed to restore respiratory function. High-resolution respirometry identified complex I dysfunction, while Blue Native-PAGE revealed defective assembly of respiratory supercomplexes. Together, these findings demonstrate that ORF7a disrupts mitochondrial metabolism through enzymatic regulation and destabilization of the respiratory chain, highlighting mitochondria as a target of SARS-CoV-2-induced metabolic reprogramming.
Keywords: CP: microbiology; ORF7a; SARS-CoV-2; complex I dysfunction; metabolic reprogramming; mitochondrial dysfunction; oxidative phosphorylation; respiratory chain supercomplexes.
. 2026 Jul 28;45(8):117755.
doi: 10.1016/j.celrep.2026.117755. Online ahead of print.
SARS-CoV-2 ORF7a drives mitochondrial dysfunction via PDK4 activation and complex I inhibition
Raúl Fernández-Rodríguez[SUP] 1 [/SUP], Carmen M Soto-Jiménez[SUP] 1 [/SUP], Rebeca Acín-Pérez[SUP] 2 [/SUP], Ana de Lucas-Rius[SUP] 3 [/SUP], Miguel Padilla-Blanco[SUP] 3 [/SUP], Luz M Sánchez-Mendoza[SUP] 4 [/SUP], Blanca D López-Ayllón[SUP] 5 [/SUP], Ángela Peralbo-Molina[SUP] 6 [/SUP], Eduardo Chicano-Gálvez[SUP] 6 [/SUP], José M Villalba[SUP] 7 [/SUP], José A Enríquez[SUP] 2 [/SUP], María Montoya[SUP] 3 [/SUP], Juan J Garrido[SUP] 1 [/SUP], Tránsito García-García[SUP] 8 [/SUP]
Affiliations
- PMID: 42519834
- DOI: 10.1016/j.celrep.2026.117755
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection reprograms host metabolism to favor viral replication and immune evasion, yet the contribution of accessory proteins remains poorly defined. Here, we characterize the metabolic effects of the SARS-CoV-2 accessory protein ORF7a. Lentiviral expression of ORF7a in human lung epithelial (A549) and monocytic (THP1) cells, combined with integrated transcriptomic, proteomic, and metabolomic analyses, revealed marked dysregulation of glucose and lipid metabolism. ORF7a impaired mitochondrial oxidative phosphorylation, reducing basal and maximal respiration, inducing mitochondrial depolarization, and increasing reactive oxygen species. Mechanistically, ORF7a upregulated pyruvate dehydrogenase kinase 4 (PDK4), enhancing phosphorylation of the pyruvate dehydrogenase complex and suppressing pyruvate oxidation. However, pharmacological PDK4 inhibition failed to restore respiratory function. High-resolution respirometry identified complex I dysfunction, while Blue Native-PAGE revealed defective assembly of respiratory supercomplexes. Together, these findings demonstrate that ORF7a disrupts mitochondrial metabolism through enzymatic regulation and destabilization of the respiratory chain, highlighting mitochondria as a target of SARS-CoV-2-induced metabolic reprogramming.
Keywords: CP: microbiology; ORF7a; SARS-CoV-2; complex I dysfunction; metabolic reprogramming; mitochondrial dysfunction; oxidative phosphorylation; respiratory chain supercomplexes.