Slater had the excellent habit of inducing his prominent visitors to sit down with one of his students. Although famous for his work on fatty acid and cholesterol biosynthesis, he had also done other work on mitochondrial metabolism and he was a real mito‐insider. Soon after the publication of this Nature letter, the Slater lab was visited by Feodor Lynen, Nobel laureate, and shrewd biochemist. Only tidbits were sent to Nature and published without peer‐review, because the editor did not consider that necessary for papers from reputable labs. High‐impact journals had not been invented yet and substantial experimental work was sent to BBA, JBC, or Biochem. This may seem incredible today, but the time was 1959. This result was sent off to Nature and published without delay. I checked this with rat‐liver mitochondria oxidizing glutamate-the favorite substrate of the time-with clear‐cut results: glutamate oxidation by isolated mitochondria required Pi, even when the mitochondria were completely uncoupled. This was an important detail, because it was not known at the time whether the postulated high‐energy intermediate in OXPHOS contained phosphate. For a further refinement of his hypothesis, Slater often asked a student to check a detail, in my case whether the respiratory chain required also inorganic phosphate (Pi) when it was uncoupled from ATP synthesis by the addition of the uncoupler dinitrophenol. One of the giants of the early history of mitochondrial metabolism and oxidative phosphorylation (OXPHOS), Slater had formulated the chemical hypothesis for the mechanism of OXPHOS (see Reference 2), which was generally accepted before Peter Mitchell entered the scene with his revolutionary chemi‐osmotic hypothesis. In looking for more fruitful topics, I ended up with the malate–aspartate shuttle (MAS).Īt the time I was a student in the lab of Bill Slater, They were certainly not uncoupled, as postulated by the formidable German Nobel laureate Otto Warburg. In vain, I tried to find anything abnormal. This illustrates the vitality of ongoing MAS research.Īs a student, I studied the properties of tumor mitochondria in Ehrlich ascites tumor cells. 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). 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 MAS is still a very active field of research. This makes the MAS in practice uni‐directional toward oxidation of cytosolic NADH, and explains why the free NADH/NAD ratio is much higher in the mitochondria than in the cytosol. 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‐motive force generated by the respiratory chain: for every aspartate effluxed, mitochondria take up one glutamate and one proton. 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. 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 ). This article presents a personal and critical review of the history of the malate–aspartate shuttle (MAS), starting in 1962 and ending in 2020.
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