Welcome to the Family: Identification of the NAD+ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25

Abstract

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD+ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD+ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD+ carrier in mammals, a long-standing mystery in NAD+ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.

Fueling genome maintenance: On the versatile roles of NAD+ in preserving DNA integrity

“…In the second (and final) step of the salvage pathway, NMN is converted to NAD + by ATP-dependent nicotinamide mononucleotide adenylyl transferase (NMNAT). This enzyme in human tissues exists in three isoforms: the most ubiquitous nuclear NMNAT1, cytoplasmic NMNAT2 ( 25 ), and mitochondrial NMNAT3, whose function remains controversial ( 26 , 27 , 28 ). In addition, NMNAT catalyzes the formation of nicotinic acid adenine dinucleotide (NAAD) from NAMN, which comes from either Preiss–Handler or de novo pathways.…”

“…Such differences in subcellular NAD + pools reflect its biological functions (see later) and are variable in tissues with different metabolic roles. Similarities in nuclear and cytoplasmic levels are likely because of the passive diffusion of NAD + and its precursors through nuclear pores ( 33 ), although the detailed relationships between nuclear and cytoplasmic pools appear to be complex, since depletion of NAD + in one compartment cannot be fully compensated by the other pool ( 28 ). As NAD + has an overall negative charge, it is unable to passively cross lipid bilayers in mitochondria and other cellular membranes.…”

Synthesis of Mixed Dinucleotides by Mechanochemistry

“…Specific transporters on the cell surface recognize and import the non-charged water-soluble vitamins that are then rapidly phosphorylated in the cytosol or exported back in the extracellular space by equilibrative transporters [ 8 , 9 , 10 , 11 ]. While transporters of extracellular phosphorylated cofactor precursors remain under intense scrutiny, specific mitochondrial membrane carriers, SLC25A19, SLC25A32, and SLC25A51, have been shown to import across the mitochondrial membrane from the cytosol ThDP, NAD and FAD, respectively, and support the sub-cellular distribution of each cofactors [ 12 , 13 , 14 ] in this organelle. Overcoming vitamin B1, B2 and B3 cofactor depletion in the mitochondrion has been the focus of much basic and clinical research in the past few years [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration‐resistant prostate cancer

“…14 The solute family 25 member 17 (SLC25A17) transports multiple cofactors like coenzyme A (CoA), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and nucleotide adenosine monophosphate (AMP). 15,16 It also catalyzes the transport of free CoA, FAD, and NAD + from the cytosol into the peroxisomal matrix thus playing a key role in regulating lipid metabolism. 16 In addition, the solute carrier family 27 member 6 (SLC27A6) is a transport protein involved in the translocation of long-chain fatty acids across the plasma membrane.…”

“…15,16 It also catalyzes the transport of free CoA, FAD, and NAD + from the cytosol into the peroxisomal matrix thus playing a key role in regulating lipid metabolism. 16 In addition, the solute carrier family 27 member 6 (SLC27A6) is a transport protein involved in the translocation of long-chain fatty acids across the plasma membrane. 17 Aberrant expression of SLC25A17 and SLC27A6 activates cellular metabolism in cancer cells and could lead to the development of drug resistance.…”