Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19

Abstract

The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, 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 hyper-inflammation, 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 following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-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 following 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.

Modulation of alveolar macrophage and mitochondrial fitness by medicinal plant-derived nanovesicles to mitigate acute lung injury and viral pneumonia

“…Dysfunctional mitochondria and distorted alveolar macrophages are critically involved in the pathogenesis of ALI and ARDS, which provides the rationale for developing mitochondria and AM-targeting treatments for severe respiratory diseases [ 12 , 13 , 15 , 16 ]. In the present study, we isolated nanovesicles from the medicinal plant, Artemisia, and demonstrated their alleviating roles in alleviating lung inflammation and injury mainly through the regulation of AMs abundance and function.…”

“…Concurrently, mitochondria are signaling hubs controlling cellular apoptosis, metabolic programs, anti-viral immunity and inflammatory responses. Therefore, maintaining mitochondrial integrity is critical for sustenance and functioning of lung resident macrophages, whereas distorted mitochondria may cause energetic exhaustion, oxidative stress and inflammatory responses leading to AMs depletion and immune imbalance that underpin critical pulmonary diseases [ 12 , 13 ]. To rectify this defect, recent attempts of “mitochondrial transfer” or “mitochondria replacement” have demonstrated promising effects [ 14 , 15 ].…”

The effects of Paxlovid on glycolipid immunometabolism in the patients with non-severe SARS-CoV-2 infection

“…Our study further indicated that inflammation status sharply decreased and lymphocyte counts statistically increased in COVID-19 patients treated by paxlovid. It may be related to the compromised mitochondrial respiration and increased HIF-1α expression in alveolar macrophages (AMs) after viral infection in vivo (13), and the inhibition of pyruvate metabolism by mitochondrial pyruvate carrier inhibitor (MSDC) enhanced mitochondrial oxidative phosphorylation (OXPHOS) and fitness, which was associated with the reduction of proinflammatory cytokines (14). Thus, paxlovid may promote mitochondrial metabolic fitness and could be a novel therapeutic avenue for COVID-19.…”

The role and intervention of mitochondrial metabolism in osteoarthritis

“…Researchers have also investigated the therapeutic potential of targeting the mitochondrial pyruvate carrier (MPC), a critical regulator of mitochondrial metabolism, for various diseases [53]. Inhibiting MPC has been found to reduce mitochondrial respiration, ROS production, and the production of inflammatory mediators [54], making it a potential therapeutic approach for OA. Additionally, activation of hypoxia-inducible factor 1-alpha (HIF-1α) has been shown to decrease inflammatory cytokine synthesis, preserve the chondrogenic phenotype, regulate glycolysis and mitochondrial function in OA, and delay cartilage degradation by promoting a denser collagen matrix [55].…”