bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–11–16
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
  2. Calcium Regulation of Mitochondrial Metabolism.
  1. Nat Metab. 2025 Nov 13.
    Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
    Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Mads M Foged, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.
      Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01419-2
  2. Annu Rev Physiol. 2025 Nov 10.
    Calcium Regulation of Mitochondrial Metabolism.
    Carmen A Mannella, Pawel Swietach, Liron Boyman.
      Mitochondrial ATP production dynamically adapts to cellular energy demands, with calcium (Ca2+) playing a crucial regulatory role. In this review, we critically evaluate the evidence for intramitochondrial Ca2+ ([Ca2+]m) sensitivity in key energy metabolic pathways, highlighting the [Ca2+]m dependence of specific mitochondrial systems. We also address the metabolic consequences of [Ca2+]m-sensitive ATP production, particularly its effects on the utilization of specific macronutrients that fuel ATP production. Next, we discuss the primary Ca2+ entry pathway into the matrix, the mitochondrial Ca2+ uniporter (MCU), its macromolecular complex structure (MCUcx), and allosteric regulation by Ca2+. Key to this regulation are specific auxiliary subunits, along with the influence of mitochondrial inner membrane architecture. While the Ca2+ signaling plays an important role, it does not fully explain the scope for regulating ATP production. Emerging evidence suggests that additional signaling systems operating alongside the Ca2+ signaling contribute to the control of mitochondrial ATP production, a topic requiring further investigation.
    DOI:  https://doi.org/10.1146/annurev-physiol-052424-082740
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