bims-celmim 2025-08-24 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–08–24
ten papers selected by
Marc Segarra Mondejar

High tide or low tide: the transport and metabolism of mitochondrial nucleotides.
Exploring the metabolic signaling network of GFPT in cancer.
Calcium Signaling and Metabolic Reprogramming in Cancer: Mechanisms and Therapeutic Implications.
The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.
The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.
Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.
Inhibition of CPT1A activates the cGAS/STING pathway to enhance neutrophil-mediated tumor abrogation in triple-negative breast cancer.
Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria.
Polyclonality and metabolic heterogeneity in a colorectal tumor model.
Renal Coenzyme A (CoA) Production Fuels Stem Cell Proliferation and Tumor Growth.

Biochem J. 2025 Aug 18. pii: BCJ20253237. [Epub ahead of print]482(16):

High tide or low tide: the transport and metabolism of mitochondrial nucleotides.

Thomas MacVicar.

  Mitochondria are multifaceted organelles that support numerous cellular metabolic pathways, including the biosynthesis of nucleotides required for cell growth and proliferation. Owing to an ancient endosymbiotic origin, mitochondria contain multiple copies of their own genome and therefore demand sufficient (deoxy)nucleotides in the mitochondrial matrix for DNA replication and transcription into RNA. Disturbed mitochondrial deoxynucleotide homeostasis can lead to a decline in mitochondrial DNA abundance and integrity, causing mitochondrial diseases with diverse and severe symptoms. Mitochondrial nucleotides are not only required for nucleic acid synthesis but also for bioenergetics and mitochondrial enzymatic activity. This review first explores how mitochondria supply energy and anabolic precursors for nucleotide synthesis and how the mitochondrial network influences the spatial control of cellular nucleotide metabolism. Then follows an in-depth discussion of the mechanisms that supply mitochondria with sufficient and balanced nucleotides and why these mechanisms are relevant to human mitochondrial disease. Lastly, the review highlights the emergence of regulated mitochondrial nucleotide supply in physiological processes including innate immunity and discusses the implications of dysregulated mitochondrial and cytosolic nucleotide homeostasis in pathophysiology.

Keywords:  metabolism; mitochondria; mitochondrial disease; nucleotide salvage; nucleotide transport; nucleotides

DOI:  https://doi.org/10.1042/10.1042/BCJ20253237
Cell Death Discov. 2025 Aug 19. 11(1): 388

Exploring the metabolic signaling network of GFPT in cancer.

Chibuzo Sampson, Pengfei Li, Yiqian Wang, Jing Liu, Jing Lv, Tian Xia, Hai-Long Piao, Yegang Ma.

Metabolic homeostasis is essential for cellular function in living organisms. In cancer cells, metabolic processes are reprogrammed to meet the energy demands and biosynthetic needs for rapid growth. This reprogramming enhances nutrient flux through the glycolytic pathway, supporting ATP production and branching into pathways that synthesize macromolecules required for cell proliferation. One critical branching pathway is the hexosamine biosynthesis pathway (HBP), which, driven by metabolic reprogramming, facilitates the synthesis of uridine-5'-diphospho-N-acetylglucosamine (UDP-GlcNAc), a glycosylation substrate. This pathway is regulated by the rate-limiting enzyme glutamine-fructose-6-phosphate transaminase (GFPT), a key controller of cellular UDP-GlcNAc levels and protein glycosylation. Dysregulation of GFPT is linked to metabolic disorders, like in diabetes, and it is also frequently upregulated in cancers. Given that GFPT plays a pivotal role in cancer metabolism, elucidating its regulatory interactions with other metabolic signaling pathways under metabolic stress is crucial to identifying therapeutic vulnerabilities in cancer. This review discusses the interaction network of GFPT with other metabolic pathways, its role in nutrient sensing, and the implications of GFPT deregulation in cancer.

DOI: https://doi.org/10.1038/s41420-025-02687-3
Cold Spring Harb Perspect Biol. 2025 Aug 18. pii: a041764. [Epub ahead of print]

Calcium Signaling and Metabolic Reprogramming in Cancer: Mechanisms and Therapeutic Implications.

Evan Courmont, Anna Rita Cantelmo.

Calcium is essential for cellular homeostasis, orchestrating a vast array of physiological processes through tightly regulated storage, flux, and signaling pathways. Dysregulation of calcium homeostasis disrupts these finely tuned processes, leading to aberrant signaling that contributes to cancer progression. Beyond its role in cellular dysfunction, calcium also regulates the metabolic reprogramming in cancer cells, enabling them to adapt their metabolism to support tumor growth, survival, and resistance. Despite its fundamental role, direct therapeutic targeting of calcium signaling in cancer remains elusive. This review explores the intricate cross talk between calcium signaling and cancer metabolism, dissecting how distinct calcium dynamics drive adaptive oncogenic adaptations. Deciphering this interplay may reveal therapeutic opportunities that leverage calcium-dependent metabolic vulnerabilities in cancer. Given its broad influence, calcium signaling regulation could serve as a multitargeting strategy for anticancer therapy, broadening the range of potential therapeutic interventions.

DOI: https://doi.org/10.1101/cshperspect.a041764
Cell Death Discov. 2025 Aug 19. 11(1): 390

The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.

Xing Yan, Changhong Liu.

At the center of tumor(neoplasm) metabolic adaptation lies activating transcription factor 4 (ATF4), a key regulator that orchestrates Glutamine (Gln) uptake, utilization, and redox balance under conditions of nutrient deprivation and oxidative stress. This review explores how ATF4 integrates environmental and cellular stress signals to drive Gln metabolic processes, enabling tumor survival, metabolic reprogramming, and immune evasion. The ATF4-Gln axis emerges as a pivotal vulnerability in cancer metabolic processes. Preclinical studies of small-molecule inhibitors and synthetic derivatives disrupting this pathway show promising results. Understanding the intricate interplay between ATF4, Gln metabolic processes, and cancer progression provides valuable insights for novel therapeutic strategies. Future research must address tumor heterogeneity and metabolic flexibility to fully harness the potential of ATF4-centered therapies. However, challenges such as off-target effects of ATF4 inhibitors and metabolic plasticity in tumors remain critical barriers. Future studies integrating multi-omics approaches and AI-driven drug discovery are warranted to overcome these hurdles.

DOI: https://doi.org/10.1038/s41420-025-02683-7
bioRxiv. 2025 Aug 12. pii: 2025.08.10.669191. [Epub ahead of print]

The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.

Thi Thinh Nguyen, Mohit Bansal, Jane Ding, Sunil Sudarshan, Han-Fei Ding.

The mevalonate pathway produces sterols and isoprenoids that support cancer cell growth, yet its broader metabolic functions remain incompletely defined. Here, we show that this pathway sustains amino acid biosynthesis by promoting mitochondrial NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impairs oxidative phosphorylation, lowers the NAD⁺/NADH ratio, and suppresses de novo serine and aspartate synthesis, thereby activating the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limits purine and pyrimidine nucleotide production. Expression of the bacterial NADH oxidase LbNOX or the alternative oxidase AOX restores NAD⁺ levels and rescues statin-induced growth inhibition. These findings suggest that impaired NAD⁺ regeneration is a key mechanism contributing to the anti-proliferative activity of statins, linking the mevalonate pathway to mitochondrial electron transport- dependent control of amino acid metabolism.
Significance: This study identifies the mevalonate pathway as a regulator of amino acid biosynthesis through mitochondrial electron transport-dependent NAD⁺ regeneration and reveals redox disruption as a key mechanism contributing to the anti-proliferative effects of statins.

DOI: https://doi.org/10.1101/2025.08.10.669191
iScience. 2025 Sep 19. 28(9): 113233

Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.

Tadahiro Shimazu, Ayane Kataoka, Takehiro Suzuki, Naoshi Dohmae, Yoichi Shinkai.

  Protein acetylation plays crucial roles in diverse biological functions, including mitochondrial metabolism. Although SIRT3 catalyzes the removal of acetyl groups in mitochondria, the addition of the acetyl groups is thought to be primarily controlled in an enzyme-independent manner due to the absence of potent acetyltransferases. In this study, we developed an engineered mitochondria-localized acetyltransferase, named engineered mitochondrial acetyltransferase (eMAT). eMAT localized in the mitochondrial matrix and introduced robust global protein lysine acetylation, including 413 proteins with 1,119 target lysine residues. Notably, 74% of the acetylated proteins overlapped with previously known acetylated proteins, indicating that the eMAT-mediated acetylation system is physiologically relevant. Functionally, eMAT negatively regulated mitochondrial energy metabolism, inhibited cell growth, and promoted cellular senescence, suggesting that mitochondrial hyper-acetylation drives metabolic inhibition and cellular senescence. SIRT3 counteracted eMAT-induced acetylation and metabolic inhibition, restored cell growth, and protected cells from senescence, highlighting the contribution of SIRT3 in maintaining energy metabolism and preventing cellular senescence.

Keywords:  Metabolic flux analysis; Metabolomics; Protein

DOI:  https://doi.org/10.1016/j.isci.2025.113233
Cancer Lett. 2025 Aug 16. pii: S0304-3835(25)00561-0. [Epub ahead of print]633 217991

Inhibition of CPT1A activates the cGAS/STING pathway to enhance neutrophil-mediated tumor abrogation in triple-negative breast cancer.

Chenglong Li, Tingfang Gao, Qiuling Zhao, Zhi Li, Zhidong Wang, Shuaishuai Ding, Mengsi Zhang, Yan Qin, Xinwen Xue, Xiao Zhang, Gan Tian, Xiu-Wu Bian, Yi Yang.

  Triple-negative breast cancer (TNBC) remains a challenging malignancy to treat, underscoring the urgent need to explore novel and effective therapeutic targets. In this study, we found that carnitine palmitoyltransferase 1A (CPT1A), the central and rate-limiting enzyme for fatty acid oxidation (FAO) in lipid metabolism, is significantly correlates with poor survival outcomes in TNBC patients and is highly expressed in TNBC patient samples. Inhibition of CPT1A greatly suppresses TNBC tumor growth. Mechanistically, we discovered that beyond disruption of the canonical metabolic functions for tumor cell survival, CPT1A depletion markedly triggers cGAS/STING activation due to lipid accumulation-induced elevation of mitochondrial reactive oxygen species (ROS), leading to mitochondrial damage and subsequent mtDNA cytosolic release, which ultimately promotes neutrophil intratumoral infiltration and acquisition of a tumor-killing phenotype, thereby effectively inhibiting tumor growth. Our current findings suggest that inhibition of CPT1A potently activates the cGAS/STING pathway, significantly enhancing the engagement of neutrophils for tumor abrogation.

Keywords:  CPT1A; Fatty acid oxidation; Neutrophils; Triple-negative breast cancer (TNBC); cGAS/STING

DOI:  https://doi.org/10.1016/j.canlet.2025.217991
Nat Commun. 2025 Aug 16. 16(1): 7651

Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria.

Tetiana Serdiuk, Yanick Fleischmann, Dhiman Ghosh, Aro Delparente, Viviane Reber, Larissa Frey, David Rhyner, Juan Gerez, Norbert Volkmar, Lucie Kralickova, Guillaume Mas, Christian Dörig, Sebastian Hiller, Roger Schibli, Linjing Mu, Paola Picotti, Roland Riek.

Mitochondrial dysfunction and accumulation of α-synuclein aggregates are hallmarks of the neurodegenerative Parkinson's disease and may be interconnected. To investigate the interplay between α-synuclein and brain mitochondria at near atomic structural level, we apply NMR and identify α-synuclein protein interactors using limited proteolysis-coupled mass spectrometry (LiP-MS). Several of the proteins identified are related to ATP synthesis and homeostasis and include subunits of ATP synthase and the adenylate kinase AK2. Furthermore, our data suggest that α-synuclein interacts with the Parkinson's disease-related protein DJ1. NMR analysis demonstrates that both AK2 and DJ1 bind to the C-terminus and other segments of α-synuclein. Using a functional assay for AK2, we show that monomeric α-synuclein has an activating effect, whereas C-terminally truncated α-synuclein and α-synuclein in an amyloid fibrillar state have no significant effect on AK2 activity. Our results suggest that α-synuclein modulates ATP homeostasis in a manner dependent on its conformation and its C-terminal acidic segment.

DOI: https://doi.org/10.1038/s41467-025-62895-4
iScience. 2025 Aug 15. 28(8): 113090

Polyclonality and metabolic heterogeneity in a colorectal tumor model.

Pierre Delamotte, Mickael Poidevin, Yan Jaszczyszyn, Arnaud Le Rouzic, Jacques Montagne.

  The monoclonal origin of cancer is widely accepted, although numerous studies suggest that some are of polyclonal origin. Loss of checkpoints in transformed cells gives rise to carcinomas comprising a wide diversity of cell types that fulfill distinct, even complementary, metabolic functions, contrasting with a hypothetical monoclonal origin. Here, using a Drosophila intestinal tumor model, we show that, despite an identical genetic background, these tumors (1) comprise a conserved set of different metabolic-specialized clusters; (2) are always polyclonal and derive from several clones characterized by distinct metabolic specificity; (3) depend on motility of the founder clones for their growth; and (4) share metabolic needs similar to those of human cancers. In summary, our study indicates that, in this model, tumor formation always requires assembly between founder clones potentially providing distinct cellular functions, as visualized by their metabolic heterogeneity. Thus, this polyclonal assembly would constitute a critical step of tumor progression.

Keywords:  Cancer; Experimental models in systems biology; Metabolic flux analysis

DOI:  https://doi.org/10.1016/j.isci.2025.113090
bioRxiv. 2025 Aug 11. pii: 2025.08.08.669325. [Epub ahead of print]

Renal Coenzyme A (CoA) Production Fuels Stem Cell Proliferation and Tumor Growth.

Ting Miao, Ying Liu, Mujeeb Qadiri, John M Asara, Yanhui Hu, Xiaomei Sun, Christian Dibble, Norbert Perrimon.

Coenzyme A (CoA), derived from Vitamin B5 (VB5), is essential for lipid metabolism, energy production, and cell proliferation. While the intracellular functions of CoA are well characterized, its tissue-specific regulation and systemic physiological roles remain poorly understood. Here, using Drosophila melanogaster , we uncover a gut-renal circuit in which dietary VB5 stimulates CoA biosynthesis specifically in the Malpighian tubules (MTs, the fly kidney), non-autonomously impacting gut homeostasis. We show that Myc boosts renal CoA production by directly upregulating Fbl ( PANK1-3 homolog) and downregulating dPANK4 in the MTs. Elevated CoA biosynthesis enhances the mevalonate-isoprenoid pathway activity in the gut, promoting intestinal stem cell proliferation. We further demonstrate that renal CoA production is required for gut tumor growth in a fly model. Consistently, MYC and genes within the CoA-isoprenoid axis display strong association with clinical outcomes in human cancers. Together, our findings establish that Myc-driven CoA metabolism generates an inter-organ signal that couples VB5 availability to stem cell control and tumor growth, and identify the CoA-isoprenoid axis as a targetable metabolic vulnerability in cancer.

DOI: https://doi.org/10.1101/2025.08.08.669325