Fig. 4: Virus-induced HMRD: hypoxia and ‘Warburg’ effect.
Dysregulation of glycolysis/TCA cycle is a key feature of HMRD. COVID-19 patients exhibit elevated serum glucose levels with an upregulation of glycolytic intermediates. Glutamine deficiency and hyaluronan over synthesis are HMRD-induced metabolic events in SARS-CoV-2 infection785. M1 macrophages express nitric oxide synthase (NOS), which oxidizes arginine to nitric oxide (NO•) and citrulline. NO• modulates vascular tone, blood pressure and hemodynamics. Disrupted arginine metabolism further down-regulates NO• synthesis, aggravates endothelial dysfunction and triggers severe coagulopathies in COVID-19184. Downstream generation of amino acids ornithine, citrulline, arginine in the circulation also indicates a severe renal dysfunction51. Degradation of sphingomyelin by acid sphingomyelinase (ASM) generates stimulatory ceramides, the docking molecules for phospholipase A2 (PLA2). The hydrolysis of phospholipids (i.e., phosphatidyl choline) by PLA2 elevates arachidonic acid levels, a precursor for broad spectrum eicosanoids produced by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. These enzymes further convert arachidonic acid to prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), which collectively contribute to the development of vascular inflammation and disease severity in COVID-19786. Virus-induced HMRD alters host lipid metabolism with major impact on sphingolipid and arachidonic acid pathways787. A decline in fat-soluble antioxidants’ vitamin E and carotenoids could compromises ROS quenching capacity in the plasma membrane, causes lipid peroxidation and OxS. Elevated serum lipase levels indicate damaging clinical outcomes in COVID-19 patients788. The virus-induced HMRD alternations to glucose, amino acid, and lipid metabolism could aggravate the severity of COVID-19 and may extend to PASC pathology.
