bims-smemid 2025-11-09 papers

FASEB Bioadv. 2025 Nov;7(11): e70071

Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.

De novo proline synthesis is a highly conserved and essential biochemical pathway in mammals. Beyond serving as a fundamental building block for proteins, proline also plays key roles in diverse cellular functions and maintaining tissue homeostasis. Over the past decade, accumulating evidence has underscored the significance of this pathway in regulating critical cellular processes, including redox balance, cell growth, signal transduction, and the synthesis of nucleotides and proteins, as well as overall cellular metabolism. The biosynthesis of proline is tightly controlled by multiple evolutionarily conserved mechanisms to ensure proper cellular function. Importantly, disruptions in proline metabolism-particularly changes in the activity or expression of enzymes involved in its synthesis and degradation-have been implicated in the onset and progression of several diseases, notably cancer and fibrosis. In this review, we highlight recent advances in understanding the regulation of de novo proline synthesis. We also examine how dysregulation of this pathway contributes to disease development and influences therapeutic outcomes. Finally, we explore the therapeutic potential of targeting proline metabolism in disease treatment.

Keywords: biochemistry; de novo synthesis; metabolism; proline

DOI: https://doi.org/10.1096/fba.2025-00147

Nat Commun. 2025 Nov 04. 16(1): 9664

Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.

Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.

DOI: https://doi.org/10.1038/s41467-025-65451-2

Mitochondrion. 2025 Nov 05. pii: S1567-7249(25)00092-3. [Epub ahead of print] 102095

Complex IV deficiency due toCOX4I1deep intronic and de novo variants results in progressive motor impairment andLeigh syndrome.

Olatz Ugarteburu, Laia Farré-Tarrats, Gerard Muñoz-Pujol, María Unceta, Javier De Las Heras, Ainhoa Garcia-Ribes, Arantza Arza-Ruesga, Belén de la Morena, Gianluca Arauz-Garofalo, Marina Gay, Gloria Garrabou, Javier Corral, Marta Vilaseca, Antonia Ribes, Judit García-Villoria, Laura Gort, Frederic Tort.

COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient's tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV.Additionally, proteomic data in patient's fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.

Keywords: COX4I1; Leigh syndrome; Long read sequencing; Proteomics; complex IV

DOI: https://doi.org/10.1016/j.mito.2025.102095

Front Genet. 2025 ;16 1690947

Multi-omics identification and validation of oxidative phosphorylation-related hub genes in schizophrenia.

Yu Zhou, Shuang Zhang, Yao-Xia Liu, Xin Dai, Ting Zhang, Xiao-Tao Xu, Sheng-Nan Deng, Min-Yan Yang, Zhen Fan.

Introduction: Dysfunction in mitochondrial oxidative phosphorylation (OXPHOS) has been implicated in the pathophysiology of schizophrenia, yet its molecular underpinnings remain poorly defined. In this study, we performed an integrative multi-omics analysis to delineate these molecular signatures.
Methods: Bulk transcriptomic datasets of schizophrenia patients and controls were obtained from the Gene Expression Omnibus. Differentially expressed genes (DEGs) associated with OXPHOS were identified through a combination of differential expression analysis, single-sample gene set enrichment analysis (ssGSEA), and weighted gene co-expression network analysis (WGCNA). Hub genes were prioritized by machine learning algorithms (LASSO, SVM-RFE, and random forest). These hub genes were validated using an independent dataset and further corroborated by RT-qPCR in an MK-801-induced mouse model. Single-nucleus RNA sequencing (snRNA-seq) was employed to delineate cell type-specific oxidative phosphorylation activity and transcriptional profiles.
Results: Transcriptomic analysis identified 130 DEGs between schizophrenia and controls, significantly enriched in oxidative phosphorylation and mitochondrial respiration pathways. Subsequent ssGSEA confirmed the reduced OXPHOS enrichment scores in schizophrenia. Furthermore, WGCNA uncovered two hub modules significantly associated with OXPHOS, which also showed strong correlations with schizophrenia. Intersecting their 2,609 module genes with 130 DEGs yielded 69 OXPHOS-related DEGs. From these, machine learning prioritized six hub genes, four of which demonstrated strong diagnostic potential and robust correlations with OXPHOS scores. Extending these findings in vivo, MK-801-treated mice exhibited behavioral and neuronal deficits, reduced ATP5A fluorescence intensity, and decreased ATP concentrations; expression of all four hub genes was significantly altered, with three (MALAT1, PPIL3, and ITM2A) concordant with transcriptomic results. Finally, snRNA-seq analysis indicated that OXPHOS is the principal ATP-generating pathway in the brain, with notable enrichment in excitatory neurons and endothelial cells, and further revealed significant correlations of MALAT1, PPIL3, and ITM2A with OXPHOS, consistent with bulk and in vivo observations.
Conclusion: This finding suggests a potential link between OXPHOS dysfunction and schizophrenia, with MALAT1, PPIL3, and ITM2A emerging as candidate regulators of this process.

Keywords: mitochondrial dysfunction; multi-omics; oxidative phosphorylation; schizophrenia; single-nucleus RNA sequencing

DOI: https://doi.org/10.3389/fgene.2025.1690947

Cell Metab. 2025 Oct 31. pii: S1550-4131(25)00437-1. [Epub ahead of print]

Cystine import and oxidative catabolism fuel vascular growth and repair via nutrient-responsive histone acetylation.

Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.

Keywords: CSE; SLC7A11; aging; cystine; epigenetics; vascular growth

DOI: https://doi.org/10.1016/j.cmet.2025.10.003