SARS-CoV-2 ORF9b exploits mitochondrial recruitment to TOMM70 for proteasomal protection and tunes inflammatory remodeling during lung infection
Abstract
Mitochondrial outer membrane proteins are exploited by diverse intracellular pathogens, to modulate cell metabolism and innate sensing pathways. Here, we demonstrate that TOMM70-dependent mitochondrial recruitment is required to protect SARS-CoV-2 ORF9b from proteasomal degradation, a dependency conserved across ORF9b homologs from related coronaviruses. ORF9b mitochondrial recruitment requires the E477 residue of TOMM70, a surface distinct from that used by the parasite Toxoplasma gondii to engage host mitochondria. We further show that TOMM70 is not a passive scaffold: its depletion activates interferon-stimulated gene expression independently of infection and remodels host immunity distinctly from ORF9b, establishing the receptor and viral protein as mechanistically separable. Using ORF9b-deficient SARS-CoV-2, we demonstrate that ORF9b is dispensable for viral replication and pathological responses in human respiratory epithelial cells and lungs of infected golden Syrian hamsters. Omics profiling of SARS-CoV-2 infected lungs revealed an induction of pathways related to COVID-19 in the absence of ORF9b. Notably, ORF9b-deficient virus-infected lungs show elevated expression of C15ORF48, a nuclear-encoded mitochondrial protein that substitutes for Complex IV subunit NDUFA4 to attenuate inflammation. Collectively, we propose that ORF9b is a receptor-gated viral protein whose principal measurable consequence during authentic infection is a restraint on inflammatory respiratory-chain remodeling.
Related
- Celastrus paniculatus seed fractions attenuate DMSO-induced neurotoxicity through mitochondrial protection and BDNF-mediated neurite growth
- Exercise-conditioned serum drives mitochondrial remodeling in neurons
- Quantitative super-resolution imaging with deep learning segmentation reveals early mitochondrial network remodeling and altered mitochondria-lysosome interactions in Pompe disease muscle
- Integrated Metabolomics Identifies Mitochondrial Dysfunction, Oxidative Membrane Remodeling, and Reduced Lipophilic Antioxidant Defenses in First-Episode Simple Dysmood Disorder
- Mitochondrial remodeling with mitochondrial fusion promoter M1 for osteoarthritis therapy.
BibTeX
@misc{zhao2026sarscov2,
title = {{SARS-CoV-2 ORF9b exploits mitochondrial recruitment to TOMM70 for proteasomal protection and tunes inflammatory remodeling during lung infection}},
author = {Yining Zhao and Lauriane Kergoat and Guilherme Dias de Melo and Florence Larrous and Guillaume Drumont and Juan Diego Hernandez Camacho and Elodie Vimont and Elodie Le Seac’h and Nell Saunders and Martin Kaechele and Etienne Kornobis and Quentin Giai Gianetto and Mariette Matondo and Isabelle Tardieux and Olivier Schwartz and Hervé Bourhy and Timothy Wai},
howpublished = {BioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.13.738231},
url = {https://pasteur.hal.science/pasteur-05742600v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - SARS-CoV-2 ORF9b exploits mitochondrial recruitment to TOMM70 for proteasomal protection and tunes inflammatory remodeling during lung infection
AU - Yining Zhao
AU - Lauriane Kergoat
AU - Guilherme Dias de Melo
AU - Florence Larrous
AU - Guillaume Drumont
AU - Juan Diego Hernandez Camacho
AU - Elodie Vimont
AU - Elodie Le Seac’h
AU - Nell Saunders
AU - Martin Kaechele
AU - Etienne Kornobis
AU - Quentin Giai Gianetto
AU - Mariette Matondo
AU - Isabelle Tardieux
AU - Olivier Schwartz
AU - Hervé Bourhy
AU - Timothy Wai
PY - 2026
DA - 2026/07/14
PB - BioRxiv
DO - 10.64898/2026.07.13.738231
UR - https://pasteur.hal.science/pasteur-05742600v1
AB - Mitochondrial outer membrane proteins are exploited by diverse intracellular pathogens, to modulate cell metabolism and innate sensing pathways. Here, we demonstrate that TOMM70-dependent mitochondrial recruitment is required to protect SARS-CoV-2 ORF9b from proteasomal degradation, a dependency conserved across ORF9b homologs from related coronaviruses. ORF9b mitochondrial recruitment requires the E477 residue of TOMM70, a surface distinct from that used by the parasite Toxoplasma gondii to engage host mitochondria. We further show that TOMM70 is not a passive scaffold: its depletion activates interferon-stimulated gene expression independently of infection and remodels host immunity distinctly from ORF9b, establishing the receptor and viral protein as mechanistically separable. Using ORF9b-deficient SARS-CoV-2, we demonstrate that ORF9b is dispensable for viral replication and pathological responses in human respiratory epithelial cells and lungs of infected golden Syrian hamsters. Omics profiling of SARS-CoV-2 infected lungs revealed an induction of pathways related to COVID-19 in the absence of ORF9b. Notably, ORF9b-deficient virus-infected lungs show elevated expression of C15ORF48, a nuclear-encoded mitochondrial protein that substitutes for Complex IV subunit NDUFA4 to attenuate inflammation. Collectively, we propose that ORF9b is a receptor-gated viral protein whose principal measurable consequence during authentic infection is a restraint on inflammatory respiratory-chain remodeling.
SN - 2692-8205
ER -