Reversal of Mitochondrial Malate Dehydrogenase 2 Enables Anaplerosis via Redox Rescue in Respiration-Deficient Cells
Open accessAbstract
Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD + , resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD + regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD + equivalents into the mitochondrion. This supports the NAD + -dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis—the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
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When the electron transport system is inhibited, reversed carbon flux through the mitochondrial dehydrogenases of Krebs cycle can provide oxidized redox equivalents to support glutamate dehydrogenase activity and cell viability.
“Additionally, when the electron transport system is inhibited, reversed carbon flux through the mitochondrial dehydrogenases of Krebs cycle can provide oxidized redox equivalents to support glutamate dehydrogenase activity and cell viability [42].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [42]
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Reductive carboxylation supports growth in tumour cells with defective mitochondria
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Silva, E. A., Dalla Costa, A. P., Ruas, J. S., Siqueira-Santos, E. S., Francisco, A., & Castilho, R. F. (2023) · Cells · doi:10.3390/cells12050683 · Cited by 5 · see citing works
- Authors
- Altea-Manzano, P., Vandekeere, A., Edwards-Hicks, J., Roldan, M., Abraham, E., Lleshi, X., Guerrieri, A. N., Berardi, D., Wills, J., Junior, J. M., Pantazi, A., Acosta, J. C., Sanchez-Martin, R. M., Fendt, S.-M., Martin-Hernandez, M., & Finch, A. J.
- Affiliations
- VIB-KU Leuven Center for Cancer Biology (BE)
- Edinburgh Cancer Research (GB)
- Queen Mary University of London (GB)
- Universidad de Granada (ES)
- Corresponding author
- Finch, Andrew J.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 82
- Issue
- 23
- Pages
- 4537-4547.e7
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4308148405
- Cited by
- 57
- References
- 6
- Citations by year
- 2026: 24 · 2025: 13 · 2024: 12 · 2023: 6 · 2022: 2
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion, cc-by)
- Institutional Repository of the University of Granada (University of Granada) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
- Mendeley Data (cc-by)
- Funders
- European Research Council (771486)
- Barts Cancer Institute
- Stichting Tegen Kanker
- Barts Charity (MGU0404)
- Fonds Wetenschappelijk Onderzoek
- Wellcome Trust
- Bayer
- H2020 Marie Skłodowska-Curie Actions
- Koning Boudewijnstichting
- International Seafood Sustainability Foundation
- Merck
- Medical Research Council
- Cancer Research UK (C355/A25137, C47559/A16243)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- anaplerosis, electron transport inhibition, NAD+ regeneration, redox signaling, succinate dehydrogenase, glutamate dehydrogenase, TCA cycle, reductive carboxylation, aspartate synthesis, cytosolic redox state
- MeSH terms
- Citric Acid Cycle, Malate Dehydrogenase, NAD, Oxidation-Reduction, Respiration
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