MT2A buffering exhaustion marks cuproptosis in severe COVID-19: Multi-omics integration, computational modeling, and experimental validation - PubMed
5 days ago
- #Cuproptosis
- #COVID-19
- #Oxidative stress
- Cuproptosis is a novel copper-dependent cell death linked to mitochondrial metabolism and protein lipoylation.
- The 'Copper Buffering-Execution Imbalance' hypothesis suggests MT2A exhaustion leads to free copper accumulation, activating the FDX1-PDH axis and triggering cuproptosis.
- Multi-omics analysis included PBMC and BALF single-cell transcriptomics and lung tissue proteomics from three datasets.
- MT2A showed discordant expression between PBMC and BALF, indicating tissue-specific regulation.
- Pseudotime analysis revealed a biphasic dynamic of MT2A: acute upregulation followed by exhaustion.
- In silico perturbation confirmed MT2A depletion activates the FDX1-PDH axis, validated in an LPS-induced mouse model.
- LUS radiomics entropy served as a macroscopic marker of oxidative damage.
- The study identifies redox checkpoints for therapeutic intervention in severe COVID-19.