bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–11–02
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
  2. A novel model for proton transport mediated by uncoupling protein 1.
  1. Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]
    Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
    Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.
      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
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.002
  2. Protein Sci. 2025 Nov;34(11): e70357
    A novel model for proton transport mediated by uncoupling protein 1.
    Luise Jacobsen, Sneha Menon, Michael James Gaudry, Ali Asghar Hakami Zanjani, Peter Reinholdt, Martin Jastroch, Himanshu Khandelia.
      Uncoupling Protein 1 (UCP1) is a mitochondrial protein which drives thermogenesis in brown adipose tissue. UCP1 facilitates the dissipation of the proton gradient as heat and plays a critical role in energy expenditure and metabolic regulation. We employ advanced molecular simulations and mutagenesis to reveal the mechanism of UCP1-mediated proton and fatty acid (FA) transport. We demonstrate that FAs bind spontaneously to UCP1's central substrate-binding site. In the binding site, a proton transfer to the FA is facilitated by a key aspartate residue (D28) and a coordinating water molecule. The protonated FA exits UCP1 through a well-defined pathway, and releases its proton into the mitochondrial matrix. UCP1 then facilitates the return of deprotonated FAs to the intermembrane space. Nucleotide binding disrupts this mechanism by inducing conformational changes in the transmembrane helices and obstructing the FA return pathway. Our mechanism explains every step of the transport cycle, is supported by simulation and biochemical data, and explains a diverse set of biochemical data about the transport mechanisms in UCP1 and its analogues: ANT, UCP2, and UCP3.
    Keywords:  UCP1; free energy calculations; mitochondrial energetics; molecular biophysics; molecular dynamics; protein dynamics; protein function; proton transport
    DOI:  https://doi.org/10.1002/pro.70357
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