Inborn disorders of the malate aspartate shuttle

Abstract

Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to the electron carrier NADH. By shuttling NADH across the mitochondrial membrane in the form of a reduced metabolite (malate), the MAS plays an important role in mitochondrial respiration. In addition, the MAS maintains the cytosolic NAD⁺ /NADH redox balance, by using redox reactions for the transfer of electrons. This explains why the MAS is also important in sustaining cytosolic redox-dependent metabolic pathways, such as glycolysis and serine biosynthesis. The current review provides insights into the clinical and biochemical characteristics of MAS deficiencies. To date, five out of seven potential MAS deficiencies have been reported. Most of them present with a clinical phenotype of infantile epileptic encephalopathy. Although not specific, biochemical characteristics include high lactate, high glycerol 3-phosphate, a disturbed redox balance, TCA abnormalities, high ammonia, and low serine, which may be helpful in reaching a diagnosis in patients with an infantile epileptic encephalopathy. Current implications for treatment include a ketogenic diet, as well as serine and vitamin B6 supplementation.

Keywords: AGC1; AGC2; GOT2; MDH1; MDH2; NAD(H); inborn metabolic disorder; malate aspartate shuttle; redox.

FIGURE 1

The malate aspartate shuttle (MAS). Cytosolic malate dehydrogenase (MDH1) transfers the reducing equivalents from NADH to oxaloacetate (OAA). This reaction generates malate (Mal) and replenishes cytosolic NAD⁺. Cytosolic malate is then transported across the inner mitochondrial membrane via the malate‐2‐oxoglutarate carrier (OGC), which exports 2‐oxoglutarate (2‐OG) from the mitochondrial matrix into the cytosol simultaneously. Next, malate is re‐oxidized by mitochondrial MDH2 to form oxaloacetate and NADH. Oxaloacetate is transaminated into aspartate (Asp) by mitochondrial aspartate aminotransferase (GOT2). This transamination reaction uses cytosolic glutamate (Glu) as nitrogen donor, which is converted into 2‐oxoglutarate. Mitochondrial aspartate is transported across the inner mitochondrial membrane via the aspartate–glutamate carrier (AGC) in exchange for cytosolic glutamate and a proton (H⁺). Lastly, aspartate is converted into oxaloacetate by cytosolic aspartate aminotransferase (GOT1) to maintain MAS activity

FIGURE 2

MAS in cellular redox metabolism. Schematic view of cellular redox metabolism involving glycolysis, serine biosynthesis, the tricarboxylic acid (TCA) cycle, the MAS and glycerol‐3 phosphate shuttle. In glycolysis, cytosolic NADH is generated by the oxidation of glyceraldehyde 3‐phosphate (GA3P) by glyceraldehyde 3‐phosphate dehydrogenase (GAPDH). GA3P can be isomerized into dihydroxyacetone phosphate (DHAP), which is converted into glycerol 3‐phosphate (G3‐P) by glycerol 3‐phosphate dehydrogenase 1(GPDH1) as part of the glycerol 3 phosphate shuttle. Serine biosynthesis branches from glycolysis at the level of 3‐phosphoglycerate (3‐PG), which is oxidized by phosphoglycerate dehydrogenase (PHGDH). Pyruvate is oxidized to lactate by lactate dehydrogenase (LDH), to sustain glycolysis by NAD⁺ regeneration. Pyruvate in the mitochondria is converted to either Acetyl‐CoA by pyruvate dehydrogenase (PDH) to enter the TCA cycle, or oxaloacetate by pyruvate carboxylase (PC) for the de novo synthesis of aspartate via glutamate‐oxaloacetate transaminase (GOT2). Within the TCA cycle NADH is generated via isocitrate dehydrogenase 3 (IDH3), oxoglutarate dehydrogenase (OGDH), and malate dehydrogenase 2 (MDH2). Malate in the TCA cycle is either derived from the conversion of fumarate or can be supplied from the cytosol via activity of the MAS. Citrate, exported from the mitochondria, is converted to oxaloacetate by ATP citrate lyase (ACLY), which in turn can be converted to malate via malate dehydrogenase 1 (MDH1). Malate can enter the mitochondria via the malate‐2‐oxoglutarate carrier or citrate carrier. Additional abbreviations: ACO, aconitase; *AT, aminotransferases; CS, citrate synthethase; FH, fumarate hydratase; GDH, glutamate dehydrogenase; GLS, glutaminase