bims-meprid 2025-03-16 papers

bioRxiv. 2025 Mar 01. pii: 2025.02.26.640389. [Epub ahead of print]

Succinate dehydrogenase activity supports de novo purine synthesis.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.

DOI: https://doi.org/10.1101/2025.02.26.640389

EMBO J. 2025 Mar 10.

Mitochondrial fatty acid oxidation regulates adult muscle stem cell function through modulating metabolic flux and protein acetylation.

Feng Yue, Lijie Gu, Jiamin Qiu, Stephanie N Oprescu, Linda M Beckett, Jessica M Ellis, Shawn S Donkin, Shihuan Kuang.

During homeostasis and regeneration, satellite cells, the resident stem cells of skeletal muscle, have distinct metabolic requirements for fate transitions between quiescence, proliferation and differentiation. However, the contribution of distinct energy sources to satellite cell metabolism and function remains largely unexplored. Here, we uncover a role of mitochondrial fatty acid oxidation (FAO) in satellite cell integrity and function. Single-cell RNA sequencing revealed progressive enrichment of mitochondrial FAO and downstream pathways during activation, proliferation and myogenic commitment of satellite cells. Deletion of Carnitine palmitoyltransferase 2 (Cpt2), the rate-limiting enzyme in FAO, hampered muscle stem cell expansion and differentiation upon acute muscle injury, markedly delaying regeneration. Cpt2 deficiency reduces acetyl-CoA levels in satellite cells, impeding the metabolic flux and acetylation of selective proteins including Pax7, the central transcriptional regulator of satellite cells. Notably, acetate supplementation restored cellular metabolic flux and partially rescued the regenerative defects of Cpt2-null satellite cells. These findings highlight an essential role of fatty acid oxidation in controlling satellite cell function and suggest an integration of lipid metabolism and protein acetylation in adult stem cells.

Keywords: CPT2; Fatty Acid Oxidation; Muscle Regeneration; Muscle Satellite Cell; Protein Acetylation

DOI: https://doi.org/10.1038/s44318-025-00397-1

Cell Rep. 2025 Mar 11. pii: S2211-1247(25)00236-0. [Epub ahead of print]44(3): 115465

Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.

Jinyang Li, Xiancheng Chen, Shiyu Song, Wangjie Jiang, Tianjiao Geng, Tiantian Wang, Yan Xu, Yongqiang Zhu, Jun Lu, Yongxiang Xia, Rong Wang.

DOI: https://doi.org/10.1016/j.celrep.2025.115465

Nat Metab. 2025 Mar 10.

A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.

Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.

DOI: https://doi.org/10.1038/s42255-025-01233-w

Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2424061122

The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8+ T cells.

Optimal activation of CD8+ T cells is crucial for immunity-mediated destruction of cancer, requiring a substantial amount of proteins involved in metabolism, proliferation, and effector function. Despite extensive studies emphasizing the role of transcriptional regulation in this process, paired transcriptomic and proteomic analyses reveal that the RNA profile is poorly correlated with protein levels. This discrepancy underscores the importance of post-translational modifications (PTMs) in controlling protein abundance during activation. However, the impact of PTMs on the CD8+ T cell protein dynamic remains underexplored. We identify that neddylation, a recently discovered PTM, is activated in response to T cell receptor (TCR) stimulation and enriched in effector CD8+ T cells from colon cancer patients. Mechanistically, we found the rate-limiting enzyme of neddylation, neural precursor cell expressed developmentally down-regulated protein 8 activating enzyme E1 (NAE1), is induced by the NFATc1, a critical transcription factor downstream of TCR signaling. Our observation revealed that genetic ablation of NAE1 significantly disturbed the proteomic landscape related to activation and mitochondrial function. As a result, CD8+ T cells lacking NAE1 exhibited severely compromised activation, proliferation, and survival, which was accompanied by impaired mitochondrial function. Consistently, deletion of NAE1 in CD8+ T cells abolished their antitumor function and promoted tumor progression. By contrast, the overexpression of NAE1 significantly improved the function of tumor-infiltrating CD8+ T cells. Overall, we uncovered neddylation, a previously underappreciated PTM, as a proteomic checkpoint for CD8+ T cell activation. Enforced expression of NAE1 offers promising therapeutic potential for boosting the antitumor CD8+ T cell responses.

Keywords: T cells; immunotherapy; post-translational modifications

DOI: https://doi.org/10.1073/pnas.2424061122