Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents: current evidence and pharmacological tools
Abstract
The malate-aspartate shuttle and the glycerol phosphate shuttle act to transfer reducing equivalents from NADH in the cytosol to the mitochondria since the inner mitochondrial membrane is impermeable to NADH and NAD+. This transfer of reducing equivalents is essential for maintaining a favorable NAD+/NADH ratio required for the oxidative metabolism of glucose and synthesis of neurotransmitters in brain. There is evidence that both the malate-aspartate shuttle and glycerol phosphate shuttle function in brain; however, there is controversy about the relative importance and cellular localization of these shuttles. The malate-aspartate shuttle is considered the most important shuttle in brain. It is particularly important in neurons and may be extremely low, or even non-existent in brain astrocytes. Several studies provide evidence of glycerol phosphate shuttle activity in brain cells; however, the activity of this shuttle in brain has been questioned. A number of pharmacological tools, including aminooxyacetic acid, beta-methyleneaspartate, phenylsuccinate, and 3-nitropropionic acid, have been used to inhibit the four enzymes and two carrier proteins that participate in the malate-aspartate shuttle. Although no drugs completely inhibit the glycerol phosphate shuttle, evidence for the existence of this shuttle is provided by studies using drugs to inhibit the malate-aspartate shuttle. This report evaluates the evidence for each shuttle in brain cells and the drugs that can be used as pharmacological tools to study these shuttles.
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Neuronal NADH:NAD+ ratio is controlled by glycolysis, lactate dehydrogenase activity, and mitochondrial NADH shuttles, mainly the malate-aspartate shuttle.
“Neuronal NADH:NAD+ ratio is controlled by three major processes (Fig. 1E): glycolysis, lactate dehydrogenase activity, and mitochondrial NADH shuttles (Salway, 2004; in neurons, mainly the malate-aspartate shuttle, McKenna et al., 2006)”
From Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake (2017) · cites this paper as McKenna et al., 2006
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- Authors
- McKenna, M. C., Waagepetersen, H. S., Schousboe, A., & Sonnewald, U.
- Affiliations
- University of Maryland, Baltimore (US)
- Norwegian University of Science and Technology (NO)
- Corresponding author
- McKenna, Mary C.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 71
- Issue
- 4
- Pages
- 399-407
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2051886358
- Cited by
- 328
- References
- 52
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 11 · 2023: 29 · 2022: 15 · 2021: 27 · 2020: 10 · 2019: 15 · 2018: 16 · 2017: 16 · 2016: 19 · 2015: 15 · 2014: 20 · 2013: 19 · 2012: 14
- FWCI
- 1.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk Fonden
- National Institutes of Health (HD16596)
- Lundbeckfonden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- malate-aspartate shuttle, glycerol phosphate shuttle, NAD+/NADH ratio, brain neurons, brain astrocytes, mitochondrial membrane permeability, aminooxyacetic acid, 3-nitropropionic acid, pharmacological inhibitors, brain energy metabolism
- MeSH terms
- Animals, Aspartic Acid, Astrocytes, Biological Transport, Cytosol, Glycerophosphates, Malates, Mitochondria, Models, Biological, NAD, Neurons, Oxidation-Reduction
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