bims-mignad 2025-10-12 papers

Issue of 2025–10–12
two papers selected by
Melisa Emel Ermert, Amsterdam UMC

Nat Commun. 2025 Oct 08. 16(1): 8952

Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.

Vidhi Pareek, Stephen Benkovic.

Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.

DOI: https://doi.org/10.1038/s41467-025-64013-w

ACS Nano. 2025 Oct 07.

Mito-Specific "Trojan Horse" Nanotherapy: Synergistic Antitumor Immunotherapy via Dual Modulation Mitochondrial Metabolism and Glycolysis.

Jingjing Yang, Mingyang Li, Zhao Wei, Jin Qian, Maoquan Chu, Zhe Qiang, Jie Ren.

Metabolic reprogramming enables tumor cells to survive and proliferate in a nutrient-deficient environment. However, the immunosuppressive tumor microenvironment caused by metabolic reprogramming is often overlooked in current metabolism interventions. Herein, we developed a mito-specific "Trojan Horse" nanoplatform (2-pN@LNPs) coloaded with Niclosamide (Nic) and 2-deoxy-d-glucose (2-DG) to attack key metabolism pathways and synergistically ignite pyroptosis for restoring antitumor immunity. 2-pN@LNPs promoted proton influx across the inner mitochondrial membrane and caused oxidative phosphorylation (OXPHOS) into a futile cycle. Furthermore, 2-pN@LNPs exploited the increased glucose demand to deliver the glycolysis inhibitor 2-DG, causing metabolic network collapse. Both cell and three-dimensional multicellular tumor spheroid results demonstrated superior synergistic metabolic intervention efficacy. The multipath metabolism deprivation leads to irreversible mitochondrial dysfunction, followed by excessive reactive oxygen species accumulation, severe adenosine triphosphate loss, and ultimately exerted a pyroptosis-like micromorphology. Moreover, the synergistic treatment regimen can promote cytotoxic and helper T cells (CD8+/CD4+ T cells) recruitment and M1-type macrophage polarization, facilitating the establishment of a boost in immunological memory to prevent recurrence and metastasis. Overall, this work provides a robust strategy targeting metabolism through mitochondrial uncoupling and glycolysis inhibition, which can effectively improve the antitumor effect, inhibit lung metastasis, and help modulate antitumor immunity.

Keywords: antitumor immunity; glycolysis inhibition; metabolic reprogramming; mitochondrial uncoupling; mitochondrial-targeted therapy

DOI: https://doi.org/10.1021/acsnano.5c08486