Biology subjects

Mullen, P. J.

Publications and source records attributed to Mullen, P. J..

6 recordsLinked to original sources

bioRxiv2026

Expression of tardigrade intrinsically disordered proteins in C. elegans reveals variable effects on aging and stress

Tardigrades survive extreme environmental stress by expressing intrinsically disordered proteins that stabilize cellular structures during cryptobiosis. Because these proteins protect cells from desiccation, oxidative stress, and DNA damage, they have attracted interest as potential therapeutics to enhance stress resilience in other organisms. However, most studies have relied on cultured cells or germline expression, leaving their effects in somatic tissues largely unexplored. Here, we generated Caenorhabditis elegans strains expressing four tardigrade intrinsically disordered proteins, Damage Suppressor (DSUP), cytoplasmic-abundant heat-soluble (CAHS), mitochondrial-abundant heat-soluble (MAHS), and Ramazzottius varieornatus late embryogenesis abundant (RvLEAM), throughout somatic tissues. Surprisingly, constitutive expression of each protein reduced lifespan, impaired motility and reproduction, and failed to improve resistance to most environmental stressors. DSUP toxicity was tissue- and developmental stage-dependent, indicating that both spatial and temporal expression influence its physiological effects. Despite these detrimental phenotypes, several proteins reduced protein aggregation during desiccation-associated stress, demonstrating context-dependent protective effects. Together, our findings reveal that tardigrade stress proteins impose physiological tradeoffs in vivo and underscore the importance of evaluating candidate stress-protective proteins in physiologically relevant somatic models before therapeutic translation.

genetics↗

bioRxiv2026

The aging mouse lipidome

Aging is associated with widespread metabolic changes that contribute to functional decline and disease. While prior studies have characterized age-associated changes in lipids, it still remains incompletely understood how the lipidome changes across tissues and between sexes during aging. Here, we performed targeted lipidomics across 10 organs collected from male and female mice at five ages spanning adolescence to old age. We analyzed 775 lipids across multiple lipid classes and found that aging affects the lipidome in an organ-specific manner. The thymus and quadriceps muscle had the most age-associated lipid changes, whereas lipid levels in organs such as the kidney and lung remained more stable. In quadriceps muscle, aging was associated with a decrease in specific phosphatidylcholine and phosphatidylethanolamine lipids, particularly those containing adrenic acid. We also identified sex-dependent differences in lipid composition, with the spleen showing differences throughout life. Spleens from female mice had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine compared to males. Together, these data provide a comprehensive atlas of age- and sex-associated lipid changes across mouse organs and complement existing metabolic and transcriptomic resources to support studies of mouse aging.

molecular biology↗

bioRxiv2024

Distinct mechanisms of non-autonomous UPRER mediated by GABAergic, glutamatergic, and octopaminergic neurons.

The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissue to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic, dopaminergic, and tyraminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways; while minor, statistically significant changes were observed in lipid metabolism-related genes with GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.

cell biology↗

bioRxiv2024

A metabolic atlas of mouse aging

Humans are living longer, but this is accompanied by an increased incidence of age-related chronic diseases. Many of these diseases are influenced by age-associated metabolic dysregulation, but how metabolism changes in multiple organs during aging in males and females is not known. Answering this could reveal new mechanisms of aging and age-targeted therapeutics. In this study, we describe how metabolism changes in 12 organs in male and female mice at 5 different ages. Organs show distinct patterns of metabolic aging that are affected by sex differently. Hydroxyproline shows the most consistent change across the dataset, decreasing with age in 11 out of 12 organs investigated. We also developed a metabolic aging clock that predicts biological age and identified alpha-ketoglutarate, previously shown to extend lifespan in mice, as a key predictor of age. Our results reveal fundamental insights into the aging process and identify new therapeutic targets to maintain organ health.

molecular biology↗

bioRxiv2020

Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by a heterogenous and densely fibrotic microenvironment. This limits functional vasculature and diffusion of nutrients through the tumor1,2. Accordingly, pancreatic cancer cells develop numerous metabolic adaptations to survive and proliferate in nutrient austere conditions3-7. Subtypes of PDA have been characterized by transcriptional and functional differences8-12, which have been reported to exist within the same tumor13-15. However, it remains unclear if this diversity extends to metabolic programming. Here, using a combination of metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses within neoplastic populations isolated from a single pancreatic tumor. Furthermore, these populations are poised for metabolic crosstalk, and in examining this, we find an unexpected role for asparagine in maintaining cell proliferation following mitochondrial inhibition. Functionally, when challenged by mitochondrial inhibition, asparagine supplementation increases intracellular levels of asparagine and aspartate, a rate limiting biosynthetic precursor16-18. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes pancreatic tumors to mitochondrial targeting with phenformin. Together, these data extend the concept of metabolic diversity to neoplastic populations within individual tumors, while illustrating a new method of intratumoral communication that supports tumor fitness19,20. Finally, the combination of asparaginase with mitochondrial inhibition could provide a powerful new strategy for this difficult to treat disease.

cancer biology↗

bioRxiv2020

Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth

Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP via the electron transport chain (ETC), respiration is required for the generation of TCA cycle-derived biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Because mTORC1 coordinates availability of biosynthetic precursors with anabolic metabolism, including nucleotide synthesis, a link between respiration and mTORC1 is fitting. Here we show that in addition to depleting intracellular aspartate, ETC inhibition depletes aspartate-derived asparagine and impairs mTORC1 activity. Providing exogenous asparagine restores mTORC1 activity, nucleotide synthesis, and proliferation in the context of ETC inhibition without restoring intracellular aspartate in a panel of cancer cell lines. As a therapeutic strategy, the combination of ETC inhibitor metformin, which limits tumour asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumour asparagine consumption, effectively impairs tumour growth in several mouse models of cancer. Because environmental asparagine is sufficient to restore proliferation with respiration impairment, both in vitro and in vivo, our findings suggest that asparagine synthesis is a fundamental purpose of mitochondrial respiration. Moreover, the results suggest that asparagine signals active respiration to mTORC1 to communicate biosynthetic precursor sufficiency and promote anabolism.

cancer biology↗