ArticleNature metabolism2026
Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
Article in Nature metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition.Nature cardiovascular research · 2026Article
- Transsulfuration links aspartate-asparagine metabolism and redox homeostasis to drive tumor growth: Asparagine-driven transsulfuration bypasses the malate-aspartate shuttle to restore redox balance, revealing a metabolic vulnerability in tumor redox maintenance.bioRxiv : the preprint server for biology · 2026Article
- Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.bioRxiv : the preprint server for biology · 2026Article
- Succinate calls a time-out on pyrimidine biosynthesis.Nature metabolism · 2026Article
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Abstract
Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.
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