Jaramillo-Martinez Valeria, Sivaprakasam Sathish, Ganapathy Vadivel, Urbatsch Ina L
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Metabolites. 2021 Sep 29;11(10):669. doi: 10.3390/metabo11100669.
INDY (I'm Not Dead Yet) is a plasma membrane transporter for citrate, first identified in . Partial deficiency of INDY extends lifespan in this organism in a manner similar to that of caloric restriction. The mammalian counterpart (NaCT/SLC13A5) also transports citrate. In mice, it is the total, not partial, absence of the transporter that leads to a metabolic phenotype similar to that caloric restriction; however, there is evidence for subtle neurological dysfunction. Loss-of-function mutations in SLC13A5 (solute carrier gene family 13, member A5) occur in humans, causing a recessive disease, with severe clinical symptoms manifested by neonatal seizures and marked disruption in neurological development. Though both INDY and mammalian INDY transport citrate, the translocation mechanism differs, the former being a dicarboxylate exchanger for the influx of citrate in exchange for other dicarboxylates, and the latter being a Na-coupled uniporter for citrate. Their structures also differ as evident from only ~35% identity in amino acid sequence and from theoretically modeled 3D structures. The varied biological consequences of INDY deficiency across species, with the beneficial effects predominating in lower organisms and detrimental effects overwhelming in higher organisms, are probably reflective of species-specific differences in tissue expression and also in relative contribution of extracellular citrate to metabolic pathways in different tissues.
INDY（我还没死呢）是一种柠檬酸的质膜转运体，最初于[具体时间或文献]中被鉴定出来。INDY的部分缺陷以类似于热量限制的方式延长了该生物体的寿命。其哺乳动物对应物（NaCT/SLC13A5）也能转运柠檬酸。在小鼠中，导致类似于热量限制的代谢表型的是该转运体的完全缺失，而非部分缺失；然而，有证据表明存在轻微的神经功能障碍。SLC13A5（溶质载体基因家族13成员A5）的功能丧失突变在人类中出现，导致一种隐性疾病，其严重临床症状表现为新生儿癫痫发作以及神经发育的明显紊乱。尽管INDY和哺乳动物的INDY都能转运柠檬酸，但转运机制不同，前者是一种二羧酸交换体，用于柠檬酸的流入并交换其他二羧酸，后者是一种与钠偶联的柠檬酸单向转运体。它们的结构也不同，从氨基酸序列中仅约35%的同一性以及理论上模拟的三维结构中便可明显看出。INDY缺陷在不同物种中产生的各种生物学后果，在低等生物中有益影响占主导，而在高等生物中有害影响占主导，这可能反映了组织表达的物种特异性差异，以及细胞外柠檬酸对不同组织代谢途径的相对贡献的差异。
