COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Figure 3

The major pathways of central metabolism and reactions that alter the ratios of coenzyme couples are shown. The mitochondrial matrix and the cytoplasm have independent coenzyme couple ratios. ATP synthesized in the mitochondrial matrix is exported to the cytoplasm in exchange for ADP by the adenine nucleotide translocase present in the inner mitochondrial membrane. Acetyl-CoA synthesized in the mitochondrial matrix must also be exported to the cytoplasm to provide two carbon units for fatty acid synthesis and protein acetylation. However, acetyl-CoA cannot cross the mitochondrial inner membrane. Therefore, the transfer of acetyl units across the inner mitochondrial membrane is accomplished using the citrate-pyruvate shuttle or the citrate-malate shuttle. These shuttles alter coenzyme levels and use inner membrane carrier proteins for the transport of citrate, pyruvate, and malate. The net result of the citrate-pyruvate shuttle on coenzyme levels is the use of energy from ATP hydrolysis and NADH oxidation to reduce NADP⁺ to NADPH. There is also a citrate-alpha-ketoglutarate shuttle system that has the net effect of using ATP hydrolysis to increase NADPH in the cytoplasm instead of increasing NADH or NADPH in the mitochondrial matrix. Synthesizing fatty acids in the cytoplasm and reducing antioxidants require NADPH. The malate-aspartate shuttle transfers reducing equivalents from NADH between the cytoplasm and the mitochondrial matrix. The glycerol 3-phosphate shuttle transfers reducing equivalents from cytoplasmic NADH to the mitochondrial ETC. Glucose is catabolized by three pathways including the hexosamine biosynthesis pathway that synthesizes uridine diphosphate (UDP) N-acetylglucosamine, glycolysis that reduces NAD⁺ to NADH and synthesizes ATP from ADP and P_i, and the pentose phosphate pathway (PPP) that reduces NADP⁺ to NADPH and synthesizes ribose sugars for nucleotide synthesis. When the pyruvate dehydrogenase complex (PDC) is inhibited, lactate is synthesized from pyruvate to recycle NAD⁺ from NADH so glycolysis can continue. However, the lactate is exported from the cell and may contribute to lactic acidosis and multiorgan failure [20]. R-BHB decreases the reliance of cells on glycolysis leading to reduced cellular lactate export. Abbreviations: Glut1 and Glut3: glucose transporters 1 and 3; MCT: monocarboxylate transporter; NNT: nicotinamide nucleotide transhydrogenase; PDC: pyruvate dehydrogenase complex.