Journal
MOLECULAR CELL
Volume 82, Issue 23, Pages 4537-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2022.10.005
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Funding
- Marie Sklodowska-Curie Actions individual fellowship
- Beug Foundation
- Fonds Wetenschappelijk Onderzoek (FWO Vlaanderen)
- MRC studentship
- Cancer Research UK Career Development Fellowship [C47559/A16243]
- European Research Council under the ERC [771486]
- FWO Projects, Fonds Baillet Latour, KU Leuven-FTBO/Internal Funding
- Stichting Tegen Kanker
- King Baudouin Foundation
- Wellcome Trust-ISSF grant
- Barts Charity [MGU0404]
- Cancer Research UK Centre Grant [C355/A25137]
- European Research Council (ERC) [771486] Funding Source: European Research Council (ERC)
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Inhibition of the electron transport chain results in the cessation of mitochondrial NAD+ regeneration and a dependence on reductive carboxylation for aspartate synthesis. However, regeneration of NAD+ in the cytosol can rescue the viability of ETC-deficient cells. This study reveals that inhibition of the ETC drives the transfer of oxidative NAD+ equivalents into the mitochondrion, supporting the activity of mitochondrial enzymes and maintaining cell viability.
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 mito-chondrial 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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