The malate-aspartate shuttle (Borst cycle): how it started and developed into a major metabolic pathway
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This article presents a personal and critical review of the history of the malate-aspartate shuttle (MAS), starting in 1962 and ending in 2020. 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-motive 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-directional 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.
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The coupling of aspartate efflux to proton import makes the malate-aspartate shuttle largely unidirectional toward glutamate import and aspartate efflux in most contexts.
“The coupling of aspartate efflux to proton import feature makes the malate–aspartate shuttle largely unidirectional toward glutamate import and aspartate efflux in most contexts (104).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [104]
The citrate-malate shuttle is coupled with an energy-expending reaction to favor cytosolic NADH oxidation.
“While both shuttles rely on MDH1 and MDH2, the citrate–malate shuttle is coupled with an energy-expending reaction to favor cytosolic NADH oxidation (104, 116).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [104]
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- Authors
- Borst, P.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Borst, Piet
- ORCID
- Borst, Piet
- Venue
- IUBMB Life
- Publisher
- Wiley
- Published
- 2020-09-11
- Volume
- 72
- Issue
- 11
- Pages
- 2241-2259
- ISSN
- 1521-6543 (ISSN-L)
- 1521-6551
- PMC
- PMC7693074
- OpenAlex
- W3085374376
- Cited by
- 252
- References
- 135
- Citations by year
- 2026: 49 · 2025: 54 · 2024: 35 · 2023: 43 · 2022: 45 · 2021: 24 · 2020: 2
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- IUBMB Life (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Radboud Universiteit
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- malate-aspartate shuttle, history of biochemistry, NADH oxidation, proton motive force, electron transport chain, MDH1, inborn errors of metabolism, cancer metabolism, mitochondrial defects, Ehrlich ascites tumor cells
- MeSH terms
- Animals, Aspartate Aminotransferases, Aspartic Acid, Humans, Malate Dehydrogenase, Malates, Metabolism, Inborn Errors, Mitochondria, Mutation, Cell Respiration
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