Citations 2
Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19
Zhu, Bibo , Wei, Xiaoqin , Narasimhan, Harish , Qian, Wei , Zhang, Ruixuan , Cheon, In Su , Wu, Yue , Li, Chaofan , Jones, Russell G. , Kaplan, Mark H. , Vassallo, Robert , Braciale, Thomas J. , Somerville, Lindsay , Colca, Jerry R. , Pandey, Akhilesh , Jackson, Patrick , Mann, Barbara J. , Sun, Jie , Vassallo, Robert , Jackson, Patrick E H , Krawczyk, Connie M , Sturek, Jeffrey M , Sun, Jie , Pandey, Akhilesh , Kaplan, Mark H , Jones, Russell G , Li, Chaofan , Somerville, Lindsay A , Zhang, Ruixuan
Science Immunology | February 23, 2023 | Volume: 8 | Issue: 82 | Pages: No page available
The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.
Structure of an AMPK complex in an inactive, ATP-bound state
Yan, Yan , Mukherjee, Somnath , Harikumar, Kaleeckal G. , Strutzenberg, Timothy S. , Zhou, X. Edward , Suino-Powell, Kelly, Xu, Ting-Hai , Sheldon, Ryan D. , Lamp, Jared , Brunzelle, J.S. , Radziwon, Katarzyna, Novick, Scott J. , Vega, Irving E. , Xu, H. Eric , Griffin, Patrick R. , Kossiakoff, Anthony A. , Melcher, Karsten , Brunzelle, Joseph S , Ellis, Abigail , Novick, Scott J , Jones, Russell G , Miller, Laurence J , Xu, H Eric , Griffin, Patrick R , Melcher, Karsten , Harikumar, Kaleeckal G , Jones, Russell G. , Miller, Laurence J.
Science | July 22, 2021 | Volume: 373 | Issue: 6553 | Pages: 413-419
How to catch a dynamic state AMP-activated protein kinase (AMPK) is a key sensor of energy status in eukaryotes. Its dynamic structure is regulated by allosteric factors including phosphorylation and binding of nucleotides and metabolites. Yan et al. developed conformation-specific antibodies that trap AMPK in a fully inactive state that has experienced a large, domain-level rotation. Biophysical experiments in cells and in vitro are consistent with the structural work and support a model in which the activation loop is fully exposed in the completely inactive, dephosphorylated state. These structures inform our understanding of the complex allosteric behavior in this crucial metabolic regulator. Science , abe7565, this issue p. 413