Asymmetric dimethylarginine is transported by the mitochondrial carrier SLC25A2

Abstract

Asymmetric dimethyl L-arginine (ADMA) is generated within cells and in mitochondria when proteins with dimethylated arginine residues are degraded. The aim of this study was to identify the carrier protein(s) that transport ADMA across the inner mitochondrial membrane. It was found that the recombinant, purified mitochondrial solute carrier SLC25A2 when reconstituted into liposomes efficiently transports ADMA in addition to its known substrates arginine, lysine, and ornithine and in contrast to the other known mitochondrial amino acid transporters SLC25A12, SLC25A13, SLC25A15, SLC25A18, SLC25A22, and SLC25A29. The widely expressed SLC25A2 transported ADMA across the liposomal membrane in both directions by both unidirectional transport and exchange against arginine or lysine. The SLC25A2-mediated ADMA transport followed first-order kinetics, was nearly as fast as the transport of the best SLC25A2 substrates known so far, and was highly specific as symmetric dimethylarginine (SDMA) was not transported at all. Furthermore, ADMA inhibited SLC25A2 activity with an inhibition constant of 0.38 ± 0.04 mM, whereas SDMA inhibited it poorly. We propose that a major function of SLC25A2 is to export ADMA from mitochondria missing the mitochondrial ADMA-metabolizing enzyme AGXT2. There is evidence that ADMA can also be imported into mitochondria, e.g., in kidney proximal tubulus cells, to be metabolized by AGXT2. SLC25A2 may also mediate this transport function.

Polarized Expression of Ion Channels and Solute Carrier Family Transporters on Heterogeneous Cultured Human Corneal Endothelial Cells

“…Interestingly, both transporters, as well as CA5, are located on the mitochondrial inner membrane. 36 , 37 It is well known that SLC25A42 protein is a mitochondrial transporter for cofactor coenzyme A (CoA) and ADP, 36 and SLC25A18 is a mitochondrial glutamate carrier 2, alternatively termed glutamate/H(+) symporter 2. 37 …”

“…Reportedly, the most important function of CAs is related to the respiration and transport of CO 2 /bicarbonate in various tissues, 60 and the primary function of SLC25A42 is probably to catalyze the entry of CoA into the mitochondria in exchange for adenine nucleotides. 37 SLC25A18 reportedly functions as a mitochondrial glutamate carrier 2 and may play a role in glutamine-mediated anaplerosis. 37 Furthermore, in this study, the observed polarized presence of transporters that provide the mitochondrial substrates was also confirmed in HCE tissues with regard to ECD in CE tissues.…”

“… 37 SLC25A18 reportedly functions as a mitochondrial glutamate carrier 2 and may play a role in glutamine-mediated anaplerosis. 37 Furthermore, in this study, the observed polarized presence of transporters that provide the mitochondrial substrates was also confirmed in HCE tissues with regard to ECD in CE tissues. The expression of CA5 and SLC25A42 was higher in HCE tissues with an ECD of >3000.…”

The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury

“…Because high levels of ADMA appear to be detrimental for mitochondrial function [ 39 ], it is reasonable to assume that the liver attempts to protect mitochondria already suffering from ischemia. Previously, elevated endogenous ADMA was found to contribute to hepatic mitochondrial dysfunction in diabetic rats and recent evidence has shown that ADMA can also be imported into mitochondria by SLC25A2 transporters [ 40 ].…”

Asymmetric dimethylarginine (ADMA) accelerates renal cell fibrosis under high glucose condition through NOX4/ROS/ERK signaling pathway

“…It is believed that CAT is the main transporter of ADMA in the kidney fibroblast. It has recently been found that mitochondrial carrier SLC25A2 is also involved in the transport of ADMA 7 . We assume that under high glucose condition, CAT could act as a main contributor in the fibroblast for transporting ADMA in and out of the cells.…”