Abstract
AbstractCitrate is produced by the tricarboxylic acid (TCA) cycle and, as a nutrient, can have both positive and negative effects on age-related disease. Citrate enters cells through plasma membrane transporters such as SLC13A5/I’m Not Dead Yet (INDY) and accumulates outside certain types of senescent cellsin vitroandin vivofollowing telomere attrition. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not clear. We show here that EC is mediated by a newly described plasma membrane citrate transporterANKH/SLC62A1(progressive human ankylosis -ANKH) in senescent fibroblasts. Analogous to interleukin 6 (IL-6), EC and/orANKHare regulated by telomere dysfunction, the p38 mitogen-activated kinase axis and transforming growth factor beta, but not by steroids or Ataxia Telangiectasia Mutated (ATM). However, the effect of sodium butyrate-induced senescence and p53 restraint on EC were variable and unrelated toANKHexpression.ANKHwas also upregulated in senescent human astrocytes, adipocytes and myoblasts, but not pre-adipocytes or keratinocytes. Neither EC norANKHwere regulated during keratinocyte differentiation. Surprisingly, EC andANKHwere inhibited in dividing and senescent fibroblasts by interleukin 1α (IL-1α) in parallel with increased IL-6 secretion. Interestingly,Ankhis downregulated in both aged mouse liver and brain tissues in parallel with increased senescence markers and the cytokines IL-1β, IL-6 and TNFα, suggesting that high levels of SASP cytokines could inhibit EC productionin vivo. These data identifyANKH/Ankhas a novel regulator of senescence-derived EC in both humans and mice.Abstract Figure
Publisher
Cold Spring Harbor Laboratory