ABCC6 in Cellular Metabolic Homeostasis: Biochemical Links to Extracellular Nucleotide Signaling, Mitochondrial Stress, and Senescence.

ABCC6 (ATP-binding cassette subfamily C member 6) was initially identified as the disease gene for pseudoxanthoma elasticum, a disorder marked by ectopic mineralization. Beyond this classical role, emerging evidence supports ABCC6 as a liver-enriched transporter with broader metabolic relevance. ABCC6 promotes hepatocyte ATP (adenosine triphosphate)/ADP (adenosine diphosphate) release and supports ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1)-dependent PPi (inorganic pyrophosphate) generation, thereby maintaining circulating anti-mineralization buffering; downstream AMP (adenosine monophosphate) metabolism may also influence adenosine-related signaling. Although its subcellular localization remains debated, evidence supports predominant basolateral plasma membrane localization, whereas one fractionation study reported enrichment at MAM (mitochondria-associated membranes) that has not been independently validated. ABCC6 deficiency has been associated with altered lipoprotein metabolism, mitochondrial bioenergetic impairment, oxidative stress, senescence-like phenotypes, and context-dependent metabolic susceptibility. These mitochondrial findings are interpreted as ABCC6 deficiency-associated downstream phenotypes rather than as evidence for stable mitochondrial or MAM residence. This review integrates established mineralization biology with emerging metabolic evidence, focusing on the extracellular nucleotide-PPi pathway, downstream adenosine-related signaling, mitochondrial stress, lipid and cholesterol handling, and vascular complications. We also discuss therapeutic strategies aimed at restoring PPi availability, limiting calcification, or recovering ABCC6 expression and function.