RT Journal Article
T1 Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
A1 Altea-Manzano, Patricia
A1 Vandekeere, Anke
A1 Edwards-Hicks, Joy
A1 Roldan, Mar
A1 Abraham, Emily
A1 Lleshi, Xhordi
A1 Guerrieri, Ania Naila
A1 Berardi, Domenica
A1 Wills, Jimi
A1 Junior, Jair Marques
A1 Pantazi, Asimina
A1 Acosta, Juan Carlos
A1 Sanchez-Martin, Rosario M
A1 Fendt, Sarah-Maria
A1 Martin-Hernandez, Miguel
A1 Finch, Andrew J
K1 anaplerosis
K1 cancer
K1 cancer metabolism
K1 metabolism
K1 mitochondrion
K1 redox
K1 redox transfer
K1 respiration
AB 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.
YR 2022
FD 2022-11-02
LK http://hdl.handle.net/10668/22394
UL http://hdl.handle.net/10668/22394
LA en
DS RISalud
RD Apr 6, 2025