[Preprint] Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10, 2023, Lopez-Ayllon et al.

Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
Blanca D. Lopez-Ayllon; Silvia Marin; Marcos Farinas Fernandez; Transito Garcia-Garcia; Raul Fernandez-Rodriguez; Ana de Lucas-Rius; Natalia Redondo; Laura Mendoza-Garcia; Carles Foguet; Jouzas Grigas; Alba Calvet; Jose Manuel Villalba; Maria Josefa Rodriguez Gomez; Diego Megias; Biagio Mandracchia; Daniel Luque; Juan Jose Lozano; Cristina Calvo; Timothy M. Thomson; Juan Jose Garrido; Marta Cascante; Maria Montoya

Antiviral signaling, immune response and cell metabolism in human body are dysregulated by SARS-CoV-2, the causative agent of the COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While all four ORFs caused mitochondrial fragmentation and altered mitochondrial function, only ORF3a and ORF9c induced a marked structural alteration in mitochondrial cristae. ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes.

In contrast, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes for proteins with critical mitochondrial functions and morphology. Genome-Scale Metabolic Models predicted common and private metabolic flux reprogramming, notably a depressed amino acid metabolism, and an enhanced metabolism of specific lipids distinctly induced by ORF3a.

These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.


Link | PDF (Preprint: BioRxiv)