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The MAS was initially proposed as a route for the oxidation of cytosolic NADH by the mitochondria in Ehrlich ascites cell tumor lacking other routes, and to explain the need for a mitochondrial aspartate aminotransferase (glutamate oxaloacetate transaminase 2 [GOT2]). The MAS was soon adopted in the field as a major pathway for NADH oxidation in mammalian tissues, such as liver and heart, even though the energetics of the MAS remained a mystery. Only in the 1970s, LaNoue and coworkers discovered that the efflux of aspartate from mitochondria, an essential step in the MAS, is dependent on the proton\u2010motive force generated by the respiratory chain: for every aspartate effluxed, mitochondria take up one glutamate and one proton. This makes the MAS in practice uni\u2010directional toward oxidation of cytosolic NADH, and explains why the free NADH\/NAD ratio is much higher in the mitochondria than in the cytosol. The MAS is still a very active field of research. Most recently, the focus has been on the role of the MAS in tumors, on cells with defects in mitochondria and on inborn errors in the MAS. The year 2019 saw the discovery of two new inborn errors in the MAS, deficiencies in malate dehydrogenase 1 and in aspartate transaminase 2 (GOT2). This illustrates the vitality of ongoing MAS research.<\/jats:p>","DOI":"10.1002\/iub.2367","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T21:05:35Z","timestamp":1603919135000},"page":"2241-2259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":262,"title":["The malate\u2013aspartate shuttle (Borst cycle): How it started and developed into a major metabolic pathway"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2527-9541","authenticated-orcid":false,"given":"Piet","family":"Borst","sequence":"first","affiliation":[{"name":"Division of Cell Biology The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,11]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(62)91120-4"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsbm.2016.0024"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/1841396a0"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsnr.2015.0029"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/185537a0"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(62)91119-8"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(61)90953-2"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)56077-4"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(63)91434-3"},{"key":"e_1_2_13_11_1","first-page":"62","article-title":"Die Wirkung von Rontgenstrahlen und Cytostatischen Verbindungen auf DPN\u2010Gehald und DNS\u2010Synthese in Ascitestumorzellen","volume":"336","author":"Hilz H","year":"1962","journal-title":"Biochem Z"},{"key":"e_1_2_13_12_1","first-page":"148","article-title":"Zum Einflu\u00df von Carcinostatica auf den DPN\u2010Stoffwechsel der Tumoren","volume":"333","author":"Kr\u00f6ger H","year":"1960","journal-title":"Biochem Z"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1979.tb04225.x"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-86784-2_10"},{"key":"e_1_2_13_15_1","first-page":"233","volume-title":"Interrelations between cytoplasmic and mitochondrial diphosphopyridine nucleotide in Ehrlich ascites tumour cells","author":"Borst P","year":"1963"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.19580701707"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.29.070160.003321"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(62)90328-5"},{"key":"e_1_2_13_19_1","first-page":"120","article-title":"Wege des Wasserstoffs in Mitochondrien I. 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