Fig. 1

Regulatory components of the adenosinergic signaling pathway. Adenosinergic signaling is regulated by multiple molecules inside and outside of cells. In the extracellular compartment, ATP and ADP can be hydrolyzed into AMP by CD39. AMP is then converted into adenosine by CD73. Extracellular adenosine can either activate AR-mediated cellular signaling through G proteins and associated effectors, degrade into inosine by ADA, or be transported across the plasma membrane through Na⁺-independent passive nucleoside transporters (i.e., ENTs) or Na⁺-dependent active nucleoside transporters (i.e., CNTs). In the intracellular compartment, ATP can be hydrolyzed into ADP and AMP by NDPK and AK, respectively. Intracellular AMP can be further converted into adenosine by cN. Intracellular adenosine can either be degraded into inosine by ADA, transported to the extracellular compartment, or resynthesized into ATP by metabolic enzymes. During the adenosine metabolism process, the elevation of the AMP-to-ATP ratio can lead to the activation of AMPK, which further modulates mitochondrial homeostasis (e.g., mitochondrial fission/fusion or mitophagy) by changing the activity of associated enzymes (e.g., MFF or ULK1). Intracellular adenosine is also associated with DNA methylation by negatively regulating transmethylation pathways. In this pathway, SAM is demethylated to SAH by DNMTs, which subsequently enhances the level of DNA methylation. SAH is then hydrolyzed into adenosine and homocysteine by SAHH. Adenosine negatively regulates the activity of SAHH, which alters the SAH level and inhibits SAM-dependent DNMT activity. ADA, adenosine deaminase; ADK, adenosine kinase; AK, adenylate kinase; AMPK, AMP-activated protein kinase; ARs, adenosine receptors; CNTs, concentrative nucleoside transporters; ENTs, equilibrative nucleoside transporters; NDPK, nucleotide diphosphokinase; NT5C/cN, endonucleotidase; SAH, S-adenosyl-homocysteine; DNMTs, DNA methyltransferases; SAHH, S-adenosyl-homocysteine hydrolase; and SAM, S-adenosyl-methionine