Biology subjects

Maddocks, O. D. K.

Publications and source records attributed to Maddocks, O. D. K..

6 recordsLinked to original sources

bioRxiv2024

Pyruvate from bone marrow mesenchymal stem cells supports myeloma redox homeostasis and anabolism

Multiple myeloma is an incurable cancer of plasma cells that depends on the bone marrow for its survival. Despite its prevalence, the molecular mechanisms underlying this malignancy remain poorly understood. In this study, we aim to bridge this knowledge gap by elucidating the metabolic interplay between myeloma cells and bone marrow mesenchymal stem cells (BMMSCs). BMMSCs are crucial in supporting myeloma cell metabolism, contributing to their proliferation, survival, and resistance to chemotherapy. Through a combination of mathematical modelling and experimental co-cultures, we demonstrate that pyruvate - the end product of glycolysis - plays a key role in myeloma cell metabolism. Our findings reveal that myeloma cells predominantly rely on the uptake of pyruvate produced by neighbouring BMM-SCs via the plasma membrane proton-linked monocarboxylate transporters MCT-1 and MCT-2 encoded by the Slc16a1 and a2 genes, respectively. Furthermore, we show that pharmacological inhibition of the MCT-1/2, with AZD3965, triggers a cascade of compensatory metabolic responses, disrupting redox balance and significantly reducing the proliferation capacity of co-cultured myeloma cells.

cancer biology↗

bioRxiv2023

Developmental mitochondrial Complex I activity determines lifespan

Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that adaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of these maladaptations could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to an 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic and metabolomic responses which overlap significantly in discreet models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits an adaptive response which severely reduces survival, while CI depletion from adulthood is not sufficient to reduce survival and stress resistance.

molecular biology↗

bioRxiv2023

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

With colorectal cancer (CRC) being the second most common cause of cancer-related deaths worldwide1, there is an urgent need for better diagnostic tools and new, more targeted therapies. Here we used genetically engineered mouse models (GEMMs), and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that unsupervised metabolic profiling can stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging (MSI) to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-mutant CRC, and propose one of its enzymes, i.e. adenosylhomocysteinase (AHCY), as a new therapeutic target. Collectively, we show that the profound genotype-dependent alterations in both lipid and small molecule metabolism in CRC may be exploited for tissue classification with no need for ion identification, and we applied further data analysis to expose a novel metabolic vulnerability of CRC.

cancer biology↗

bioRxiv2021

ROS signalling requires uninterrupted electron flow and is lost during ageing in flies

Mitochondrial Reactive Oxygen Species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) by respiratory complex I generates high levels of mtROS. Suppression of ROS produced via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We found that ROS-RET is abolished in old fruit flies where electron flux is reduced. Instead, mitochondria in aged flies produce consistently high levels of mtROS. Finally, we demonstrate that in young flies reduction of electron exit from the ETC, but not electron entry, phenocopies mtROS generation observed in old individuals. Our results define the mechanism by which ROS signalling is lost during ageing. HighlightsO_LIROS-RET signalling requires an uninterrupted flow of electrons through the ETC. C_LIO_LIROS-RET signalling fails during ageing, with mitochondria producing persistently high levels of ROS. C_LIO_LIInterruption of ROS-RET signalling compromises stress adaptation in old flies. C_LIO_LIReducing electron exit suppresses ROS-RET signalling and phenocopies ROS production observed in old mitochondria. C_LI

physiology↗

bioRxiv2020

Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

Autophagy is an essential catabolic process that promotes clearance of surplus or damaged intracellular components1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites during periods of starvation2. Loss of autophagy is sufficient to cause cell death in animal models and is likely to contribute to tissue degeneration in a number of human diseases including neurodegenerative and lysosomal storage disorders3-7. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified a critical role of autophagy in the maintenance of nicotinamide adenine dinucleotide (NAD+/NADH) levels. In respiring cells, loss of autophagy caused NAD(H) depletion resulting in mitochondrial membrane depolarisation and cell death. We also found that maintenance of NAD(H) is an evolutionary conserved function of autophagy from yeast to human cells. Importantly, cell death and reduced viability of autophagy-deficient animal models can be partially reversed by supplementation with an NAD(H) precursor. Our study provides a mechanistic link between autophagy and NAD(H) metabolism and suggests that boosting NAD(H) levels may be an effective intervention strategy to prevent cell death and tissue degeneration in human diseases associated with autophagy dysfunction.

cell biology↗

bioRxiv2019

Metabolic cross-feeding allows a gut microbial community to overcome detrimental diets and alter host behaviour

The impact of commensal bacteria on the host arises from complex microbial-diet-host interactions. Mapping metabolic interactions in gut microbial communities is therefore key to understand how the microbiome influences the host. Here we use an interdisciplinary approach including isotope-resolved metabolomics to show that in Drosophila melanogaster, Aceto-bacter pomorum (Ap) and Lactobacillus plantarum (Lp) establish a syntrophic relationship to overcome detrimental host diets and identify Ap as the bacterium altering the hosts feeding decisions. Specifically, we show that Lp generates lactate which is used by Ap to produce and provide amino acids that are essential to Lp allowing it to grow in imbalanced diets. Lactate is also necessary and sufficient for Ap to alter the flys protein appetite. Our data show that gut bacterial communities use metabolic interactions to become resilient to detrimental host diets and to ensure the constant flow of metabolites used by effector bacteria to alter host behaviour.

neuroscience↗