Biology subjects

Corbet, C.

Publications and source records attributed to Corbet, C..

4 recordsLinked to original sources

bioRxiv2026

Mitochondrial dysfunction as a hallmark of brain senescence in telomerase-deficient mice

Neurodegenerative diseases, including Alzheimer's disease (AD), are strongly associated with aging. However, the molecular mechanisms underlying pathological brain aging remain incompletely understood. In this study, we used a mouse model of telomere attrition, a major driver of cellular senescence, to perform an unbiased analysis of how telomere-driven senescence affects cellular physiology and contributes to processes relevant to neurodegenerative conditions. After validating the presence of senescence hallmarks in telomerase-deficient brains, we characterized their transcriptomic and proteomic profiles. Mitochondrial function and associated energy metabolism emerged as the major dysregulated pathways, driven predominantly by proteomic rather than transcriptomic changes. Functional biochemical analyses on isolated brain mitochondria demonstrated impaired electron transport chain (ETC) complex activity and reduced energetic status, despite preserved ETC complex integrity and mitochondrial content. Further analyses in senescent primary neurons indicated an accumulation of dysfunctional mitochondria, characterized by increased reactive oxygen species (ROS) production and reduced ATP levels, although basal cellular respiration was maintained. At the tissue level, these alterations were associated with moderate reductions in neuronal density in the subiculum and cortical layer V, indicating region-specific vulnerability rather than widespread neurodegeneration. We propose that a major consequence of telomere dysfunction associated with pathological brain aging is the downregulation of mitochondrial activity, which contributes to the selective vulnerability of specific brain regions. These findings highlight mitochondrial pathways as attractive targets for interventions aimed at preserving brain health during aging.

neuroscience↗

bioRxiv2025

UCL-MetIsoLib: A Public High-Resolution Tandem Mass Spectrometry Library for HILIC-Based Isomer-Resolved Profiling of Glycolysis, Central Carbon Metabolism, and Beyond in Urine, Plasma, Tissues, Cells, and Patient-Derived Organoids

We present UCL-MetIsoLib, a publicly accessible high-resolution tandem mass spectrometry (HRMS/MS) library developed for HILIC-based, ion-pairing free, isomer-resolved metabolomics using a bioinert UHPLC system and the Acquity Premier BEH Amide column. The platform integrates two complementary methods operating under distinct chromatographic conditions (pH 3.5, ESI+; pH 11.0, ESI-), enabling broad metabolic coverage. A total of 334 metabolites are annotated in the library structure, with thiol derivatization incorporated into the extraction protocol to mitigate redox-driven artifacts. Metabolite identification is supported by 245 authentic reference standards and curated according to MSI Level 1 and Level 2 criteria. Validation followed FDA guidelines for bioanalytical method validation and was performed across five biological matrices--urine, plasma, tissues, cultured cells, and patient-derived colorectal organoids--with a U-13C, U-15N-labeled Amino Acid Mixture used as an isotope labeled internal standard. The method demonstrated high precision (<15% RSD intra-/inter-day) and recovery (85-115% across all QC levels). To demonstrate biological applicability, UCL-MetIsoLib was applied to a case study comparing healthy and colorectal cancer-derived organoids. The method enabled confident annotation of metabolite isomers, including key glycolytic intermediates such as DHAP and GA3P, as well as sugar phosphates from the glycolysis and pentose phosphate pathways. Metabolic alterations were observed in tumor organoids, including accumulation of nucleotide derivatives and shifts in central carbon metabolism. These findings emphasize the value of isomer-resolved spectral libraries in detecting biologically meaningful differences that are often missed in conventional untargeted metabolomics workflows.

systems biology↗

bioRxiv2025

Human mitochondrial DNA variants influence telomere length: evidence from a transmitochondrial cybrid model

Telomere shortening is a hallmark of aging, yet telomere length (TL) varies considerably among individuals and is strongly influenced by inheritance. In mice, efficient mitochondrial function-characterized by low reactive oxygen species (ROS) production-is critical for telomere elongation during early embryogenesis. Since mitochondrial DNA (mtDNA) encodes several subunits of the electron transport chain, it may influence TL at birth by regulating mitochondrial function in utero. To explore the relationship between mtDNA and TL in human, we used a transmitochondrial cybrid approach, introducing mitochondria from donor platelets with varying telomere lengths into mtDNA-depleted cells. This revealed an inverse correlation between donor blood TL and mitochondrial ROS levels measured in the resulting cybrids, suggesting that specific mtDNA variants may contribute to the maintenance of long telomeres in humans by enhancing mitochondrial fitness. During in vitro cybrid formation, a transient phase of oxidative stress precedes cellular adaptation. In this specific window, mtDNA variants associated with reduced complex I (CI) activity induced rapid telomere shortening--an effect rescued by antioxidant and NAD precursor supplementation. While these variants occur naturally in certain individuals with long telomeres, our data suggest that, at least under in vitro conditions of acute oxidative stress, CI is critical to support PARP1 activity by maintaining the NAD/NADH balance, thereby preserving telomere integrity. Collectively, these findings solidify the link between mtDNA variants and human TL regulation, highlighting potential therapeutic opportunities for mitochondrial replacement strategies. Significance StatementTelomere length at birth influences aging trajectories and disease risk later in life, yet the mechanisms governing this trait remain incompletely understood. Using a transmitochondrial cybrid approach, we show that single-nucleotide variants in the mitochondrial genome of healthy donors directly affect mitochondrial metabolism and reactive oxygen species production. In addition, mitochondrial ROS levels measured in cybrids inversely correlate with blood cell telomere length in donors. During cybrid formation, mitochondrial DNA variants associated with reduced CI activity promote telomere shortening. Attrition was reversed by antioxidant and NAD precursor supplementation, pointing to an essential role for robust CI function in sustaining telomere length during acute oxidative stress, at least under in vitro conditions. Together, these findings establish a direct link between mitochondrial genetics, redox homeostasis, and telomere maintenance in human cells.

cell biology↗

bioRxiv2021

Prediction of Whole-Cell Transcriptional Response with Machine Learning

Applications in synthetic and systems biology can benefit from measuring whole-cell response to biochemical perturbations. Execution of experiments to cover all possible combinations of perturbations is infeasible. In this paper, we present the host response model (HRM), a machine learning approach that takes the cell response to single perturbations as the input and predicts the whole cell transcriptional response to the combination of inducers. We find that the HRM is able to qualitatively predict the directionality of dysregulation to a combination of inducers with an accuracy of >90% using data from single inducers. We further find that the use of known prior, known cell regulatory networks doubles the predictive performance of the HRM (an R2 from 0.3 to 0.65). This tool will significantly reduce the number of high-throughput sequencing experiments that need to be run to characterize the transcriptional impact of the combination of perturbations on the host.

bioinformatics↗