fig1

Figure 1. Energy metabolism pathways for lactate, adenosine, and NAD⁺. Pyruvate is generated predominantly through glycolysis, but the TCA cycle also contributes to pyruvate production via conversion from malate. LDH catalyzes the reaction to convert pyruvate to lactic acid, which dissociates into H⁺ and lactate ions that are exported and imported through MCTs. Alternatively, pyruvate can be converted to acetyl-CoA to participate in the TCA cycle to drive energy metabolism. In the TIME, H⁺ contributes to the low pH and lactate facilitates a variety of intracellular signaling pathways by binding to HCAR1. Extracellular adenosine is formed through both the canonical and non-canonical pathways. The canonical pathway utilizes CD39 to convert ATP or ADP to AMP and CD73 to convert AMP to adenosine. The non-canonical pathway metabolizes NAD⁺ to ADPR through CD38, ADPR to AMP through CD203a, and finally, AMP to adenosine via CD73. Extracellular adenosine binds to P1 to initiate intracellular signaling pathways or is imported through NTs. Note: adenosine generated by the canonical and non-canonical pathways participates in both P1 signaling and NT import. NAD⁺ is formed through the Preiss-Handler pathway, de novo synthesis, salvage pathway, and various enzymatic reactions in energy metabolism, such as PEP to pyruvate. The Preiss-Handler pathway imports NA and forms NAD⁺ through a series of enzymatic reactions. Do novo synthesis of NAD⁺ results from the metabolism of tryptophan and the salvage pathway recycles NAM to regenerate intracellular NAD⁺ levels. NAD⁺ serves as a co-factor for many enzymes and participates in redox reactions, such as pyruvate to lactic acid. Ado: Adenosine; ADP: adenosine diphosphate; ADPR: adenosine diphosphate ribose; AMP: adenosine monophosphate; ATP: adenosine triphosphate; GLUT: glucose transporter; G3P: glycerol-3-phosphate; H⁺: hydrogen; HCAR1: hydroxycarboxylic acid receptor 1; LDH: lactate dehydrogenase; MCTs: monocarboxylate transporters; NA: nicotinic acid; NAAD: nicotinic acid adenine dinucleotide; NAD⁺: nicotinamide adenine dinucleotide; NADS: NAD⁺ synthetase; NAM: nicotinamide; NaMN: nicotinic acid mononucleotide; NAMPT: nicotinamide phosphoribosyltransferase; NAPRT: nicotinic acid phosphoribosyltransferase; NMNAT: nicotinamide mononucleotide adenylyltransferase; NMN: nicotinamide mononucleotide; NTs: nucleoside transporters; PARP: poly (ADP-ribose) polymerase; PEP: phosphoenolpyruvate; P1: type 1 purinergic receptors; TCA: tricarboxylic acid; 1,3-BPG: 1,3-Bisphosphoglycerate.