Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells

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...

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Veröffentlicht in:Molecular cell 2022-12, Vol.82 (23), p.4537-4547.e7
Hauptverfasser: Altea-Manzano, Patricia, Vandekeere, Anke, Edwards-Hicks, Joy, Roldan, Mar, Abraham, Emily, Lleshi, Xhordi, Guerrieri, Ania Naila, Berardi, Domenica, Wills, Jimi, Junior, Jair Marques, Pantazi, Asimina, Acosta, Juan Carlos, Sanchez-Martin, Rosario M., Fendt, Sarah-Maria, Martin-Hernandez, Miguel, Finch, Andrew J.
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •GDH is inhibited in ETC-deficient cells due to reduced mitochondrial NAD+/NADH ratio•Electron acceptors rescue mitochondrial redox defects via reversal of GOT2 and MDH2•Reversed flux through MDH2 provides the NAD+ required for GDH to mediate anaplerosis•ETC deficiency and loss of MDH2 may be an effective combination for cancer therapy Cancer cells show remarkable metabolic plasticity to overcome inhibition of respiration, limiting its efficacy in cancer therapy. Altea-Manzano et al. show that reversed flux through GOT2 and MDH2 rescues mitochondrial redox imbalance and supports cell viability by promoting NAD+-dependent activity of GDH. Targeting MDH2 may complement therapeutic inhibition of respiration.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2022.10.005