2. Academic Validation
  3. Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle

  • Mol Cell. 2025 Oct 28:S1097-2765(25)00819-6. doi: 10.1016/j.molcel.2025.10.002.
Mushtaq A Nengroo 1,  Austin T Klein 1,  Heather S Carr 1,  Olivia Vidal-Cruchez 1,  Umakant Sahu 1,  Daniel J McGrail 2,  Nidhi Sahni 3,  Niklas B Thompson 4,  Peter A Faull 5,  Peng Gao 6,  John M Asara 7,  Hardik Shah 4,  Marc L Mendillo 8,  Issam Ben-Sahra 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 2 Center for Immunotherapy and Precision Immuno Oncology, Cleveland Clinic, Cleveland, OH 441796, USA.
  • 3 Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4 Metabolomics Platform, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL 60637, USA.
  • 5 Northwestern University Proteomics Core, Chicago, IL 60611, USA.
  • 6 Metabolomics Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 7 Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 8 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. Electronic address: mendillo@northwestern.edu.
  • 9 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. Electronic address: issam.ben-sahra@northwestern.edu.
PMID: 41161310 DOI: 10.1016/j.molcel.2025.10.002
Abstract

The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of Mitochondrial Metabolism in modulating this process remains underexplored. Here, we identify that Succinate Dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, Cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in Cancer.

Keywords

TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate.

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