[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Malate–aspartate shuttle [Biochemistry](https://durgical.com/en/biochemistry/) · Metabolic pathway # Malate–aspartate shuttle NADH cannot cross the inner mitochondrial membrane. This shuttle carries its electrons inside on malate, so liver and heart get the full ATP yield. Updated 2026-11-01 ## Interactive map ## Key facts - Cytosolic NADH reduces oxaloacetate to malate; malate enters the matrix and is reoxidised, giving NADH back inside. - The electrons enter the chain at complex I, so each cytosolic NADH is worth about 2.5 ATP (about 1.5 with the glycerol-3-phosphate shuttle). - It needs two antiporters and two pairs of isoenzymes (MDH1/MDH2 and AST1/AST2); nitrogen travels on aspartate and glutamate. - The aspartate–glutamate carrier is electrogenic and uses the proton gradient, which makes the shuttle run one way. - It is most active in liver, heart and kidney; skeletal muscle and brain rely more on the glycerol-3-phosphate shuttle. ## Regulation - Cytosolic Ca²⁺ activates the aspartate–glutamate carriers (aralar, citrin). - A high NADH/NAD⁺ ratio in the matrix slows the shuttle. - Aminooxyacetate blocks the aminotransferases and stops the shuttle (experimental). ## The steps, one by one - **Step 1 · Malate dehydrogenase 1 (cytosolic, MDH1)** oxaloacetate + NADH ⇌ malate + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) In the cytosol it uses NADH from glycolysis to reduce oxaloacetate to malate, giving NAD⁺ back to glycolysis. **If it fails:** If this step cannot keep up, cytosolic NAD⁺ runs short and cells turn more pyruvate into lactate. [Lactic acidosis →](https://durgical.com/en/conditions/lactic-acidosis/) - **Step 2 · 2-Oxoglutarate/malate carrier (OGC, SLC25A11)** malate + α-Ketoglutarate (matrix) ⇌ Malate (matrix) + α-ketoglutarate Swaps cytosolic malate for matrix α-ketoglutarate across the inner membrane without spending energy. **If it fails:** Inherited SLC25A11 variants predispose to paraganglioma (UniProt: PPGL6). [Hereditary paraganglioma and pheochromocytoma (SDH) →](https://durgical.com/en/conditions/hereditary-paraganglioma-and-pheochromocytoma/) - **Step 3 · Malate dehydrogenase 2 (mitochondrial, MDH2)** Malate (matrix) + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) ⇌ Oxaloacetate (matrix) + NADH In the matrix it reoxidises malate and gives NADH that feeds complex I; it is the same reaction as the last step of the Krebs cycle. **If it fails:** Biallelic MDH2 variants cause an early-onset developmental and epileptic encephalopathy (DEE51). - **Step 4 · [Aspartate aminotransferase 2 (mitochondrial, GOT2)](https://durgical.com/en/biochemistry/enzymes/aspartate-aminotransferase/)** Oxaloacetate (matrix) + Glutamate (matrix) ⇌ Aspartate (matrix) + α-Ketoglutarate (matrix) Moves the amino group of glutamate onto oxaloacetate to make aspartate, which can leave the matrix (oxaloacetate cannot). **If it fails:** Mitochondrial AST leaks into the blood in severe liver injury; an AST/ALT ratio above 2 suggests alcohol-related liver disease. - **Step 5 · Aspartate–glutamate carrier (aralar SLC25A12, citrin SLC25A13)** irreversible Aspartate (matrix) + [Glutamate](https://durgical.com/en/biochemistry/molecules/glutamate/) → Aspartate (cytosol) + Glutamate (matrix) Exports aspartate in exchange for glutamate plus a proton; because it uses the proton gradient, the shuttle cannot run backwards. **If it fails:** Citrin deficiency (SLC25A13): neonatal cholestasis, and in adults citrullinaemia type II with hyperammonaemia and a liking for protein-rich, low-carbohydrate food. [Hyperammonaemia →](https://durgical.com/en/conditions/hyperammonaemia/) - **Step 6 · [Aspartate aminotransferase 1 (cytosolic, GOT1)](https://durgical.com/en/biochemistry/enzymes/aspartate-aminotransferase/)** Aspartate (cytosol) + α-ketoglutarate ⇌ oxaloacetate + [Glutamate](https://durgical.com/en/biochemistry/molecules/glutamate/) In the cytosol it turns aspartate back into oxaloacetate, ready to take the next NADH, and makes glutamate again. **If it fails:** Cytosolic AST is most of the AST measured in serum; it rises in liver and muscle injury. ## Clinical notes - Citrin deficiency (SLC25A13): neonatal intrahepatic cholestasis, and in adults citrullinaemia type II with hyperammonaemia. - Ethanol oxidation floods the cytosol with NADH, which depends on the shuttles to be cleared. - Glycolysis needs cytosolic NAD⁺; when shuttles cannot keep up, cells reduce pyruvate to lactate instead. - AST leaks from damaged liver and heart cells; the mitochondrial isoenzyme rises with severe hepatocellular injury. ## Pathways - [Malate–aspartate shuttle](https://durgical.com/en/biochemistry/pathways/malate-aspartate-shuttle/) ## Related conditions - [Hyperammonaemia](https://durgical.com/en/conditions/hyperammonaemia/) - [Lactic acidosis](https://durgical.com/en/conditions/lactic-acidosis/) - [Hereditary paraganglioma and pheochromocytoma (SDH)](https://durgical.com/en/conditions/hereditary-paraganglioma-and-pheochromocytoma/) ## Related - [Mitochondrial NADH shuttles](https://durgical.com/en/biochemistry/topics/mitochondrial-nadh-shuttles/) - [Electron transport chain and oxidative phosphorylation](https://durgical.com/en/biochemistry/pathways/electron-transport-chain-and-oxidative-phosphorylation/) - [Complex I (NADH dehydrogenase)](https://durgical.com/en/biochemistry/enzymes/complex-i/) - [Aspartate aminotransferase (AST, GOT)](https://durgical.com/en/biochemistry/enzymes/aspartate-aminotransferase/) - [Glutamate (glutamic acid)](https://durgical.com/en/biochemistry/molecules/glutamate/) - [NAD⁺ (nicotinamide adenine dinucleotide)](https://durgical.com/en/biochemistry/molecules/nad/) - [Glycolysis](https://durgical.com/en/biochemistry/pathways/glycolysis/) - [Gluconeogenesis](https://durgical.com/en/biochemistry/pathways/gluconeogenesis/) - [Urea cycle](https://durgical.com/en/biochemistry/pathways/urea-cycle/) - [Ethanol metabolism](https://durgical.com/en/biochemistry/pathways/ethanol-metabolism/) ## Test yourself Think of the answer, then tap the question to see it. ## Why does the cell need a shuttle for cytosolic NADH? The inner mitochondrial membrane has no NADH carrier, so the shuttle moves the electrons on malate instead. ## About how many ATP does one cytosolic NADH give through this shuttle? About 2.5, because NADH is remade in the matrix and enters at complex I; the glycerol-3-phosphate shuttle gives about 1.5 through FADH₂. ## Why must oxaloacetate be converted to aspartate in the matrix? There is no oxaloacetate carrier; aspartate leaves on the aspartate–glutamate carrier and is turned back into oxaloacetate in the cytosol. ## Which inherited disorder of this shuttle causes hyperammonaemia? Citrin deficiency (SLC25A13), the liver aspartate–glutamate carrier; less aspartate reaches the urea cycle. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/malate-aspartate-shuttle/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [SLC25A13 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/slc25a13/) (MedlinePlus, US National Library of Medicine, 2026); [Malate dehydrogenase, mitochondrial (MDH2) - Homo sapiens](https://www.uniprot.org/uniprotkb/P40926/entry) (UniProt, 2026); [Mitochondrial 2-oxoglutarate/malate carrier protein (SLC25A11) - Homo sapiens](https://www.uniprot.org/uniprotkb/Q02978/entry) (UniProt, 2026); [Malate dehydrogenase, cytoplasmic (MDH1) - Homo sapiens](https://www.uniprot.org/uniprotkb/P40925/entry) (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011). [← All of biochemistry](https://durgical.com/en/biochemistry/) ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/biochemistry/pathways/malate-aspartate-shuttle/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/malate-aspartate-shuttle/