Author response: Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells

Résumé

The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD +to NADH and anabolic production of aspartate, a key amino acid for cell proliferation.Several TCA cycle components are implicated in tumorigenesis, including loss-of-function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking.Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation.Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI).We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine.We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis.These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness. Editor's evaluationMutations in subunits of succinate dehydrogenase (SDH) are implicated in tumorigenesis, but it is not fully understood how cell proliferation occurs in cells that lack SDH.Hart et al. elegantly demonstrate that lack of mitochondrial complex I increases proliferation in cells lacking SDH.The authors have expertly dissected the mechanism behind the rescue and show that inhibition of complex I restores aspartate production by modulating NAD+/NADH.This study thus demonstrates that compartmentalized redox changes control distinct aspartate biosynthetic pathways that promote the proliferation of tumor cells.

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