Biology subjects

Mahoney, J.

Publications and source records attributed to Mahoney, J..

6 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte prohibitin ablation reprograms cardiac metabolism revealing a pathogenic role for mTORC1 in dilated cardiomyopathy

Maintaining cardiac structure and function throughout the lifespan requires a delicate balance in carbon allocation between energetic and biosynthetic processes. At the nexus of this balance are prohibitins-1 and -2 (PHB1, 2) which form a ring-like complex in mitochondrial and plasma membranes responsible for coordinating cellular growth, metabolism and autophagy. Here we describe how ablation of the PHB complex in cardiomyocytes of adult mice (cPHB1KO) causes unrestrained mechanistic target of rapamycin complex 1 (mTORC1) activity and a Warburg-like reprogramming of glucose metabolism in heart toward enhanced de novo amino acid biosynthesis. These changes are accompanied by disruptions in mitochondrial Ca2+ handling and impaired autophagy, leading to severe dilated cardiomyopathy and mortality within 12 weeks. Using pharmacological and nutritional approaches, we further show that mTORC1 inhibition attenuates pathologic cardiac remodeling only in female cPHB1KO mice. Our findings illustrate novel mechanisms linking the PHB complex with altered carbon flux and pathogenesis of cardiomyopathy.

cell biology↗

bioRxiv2025

Circuit specific specialization of human basal ganglia astrocytes

Astrocytes shape synapses and circuits, yet human basal ganglia astrocyte diversity is incompletely defined. We built a multimodal atlas by integrating single-nucleus RNA-sequencing and chromatin accessibility with DNA methylation, 3D chromatin conformation, and spatial transcriptomics, then mapped basal ganglia programs onto a whole-brain reference. Astrocytes segregated into three anatomical subgroups spanning striatal gray matter, extra-striatal gray matter, and white matter, with subgroup-biased neurotransmitter transporters and synapse-associated programs consistent with differences in dominant afferent input. Within striatum, dorsal and ventral astrocyte populations aligned with distinct microcircuits and were conserved in nonhuman primates. A deep learning sequence model identified subgroup-associated enhancer code and, when benchmarked against published enhancer-AAV datasets, supported the design of candidate viral tools to target basal ganglia astrocyte programs in vivo. Together, these data define major axes of human astrocyte specialization and provide a framework for cell type-specific dissection of basal ganglia function.

neuroscience↗

bioRxiv2022

Stable iPSC-derived NKX2-1+ Lung Bud Tip Progenitor Organoids Give Rise to Airway and Alveolar Cell Types

Bud tip progenitors (BTPs) in the developing lung give rise to all epithelial cell types found in the airways and alveoli. The current work aimed to develop an iPSC organoid model enriched with stable NKX2-1+ BTP-like cells. Building on prior work, we optimized a directed differentiation paradigm to generate spheroids with robust NKX2-1 expression. Spheroids were expanded into organoids that possessed NKX2-1+/CPM+ BTP-like cells, which increased in number over time. Single cell RNA-sequencing analysis revealed a high degree of transcriptional similarity between induced BTPs (iBTPs) and in vivo BTPs. Using FACS, iBTPs can be purified and expanded as induced bud tip organoids (iBTO), which maintain an enriched population of bud tip progenitors. When iBTOs are directed to differentiate into airway or alveolar cell types using well-established methods, they give rise to organoids composed of organized airway or alveolar epithelium, respectively. Collectively, iBTOs are transcriptionally and functionally similar to in vivo BTPs, providing an important model to study human lung development and differentiation. SUMMARY STATEMENTiPSC-derived lung bud tip progenitors emerge in organoid culture, can be isolated and expanded, are transcriptionally similar to primary bud tip progenitors, and can differentiate into airway or alveolar organoids.

developmental biology↗

bioRxiv2021

A multimodal iPSC platform for cystic fibrosis drug testing

Cystic fibrosis (CF) is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane regulator (CFTR) anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of the CFTR channel using established animal and cell-based models led to the recent discovery of effective CFTR modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we assembled a panel of iPSCs derived from individuals with common or rare variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function in patient-specific iPSCs we adapted two established in vitro assays of CFTR function to iPSC-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we quantified CFTR baseline function and response to CFTR modulators and detected genotype-specific differences. Our results demonstrate the potential of the human iPSC platform as a research tool to study cystic fibrosis and in particular accelerate therapeutic development for CF caused by rare mutations.

developmental biology↗

bioRxiv2020

A molecular atlas of proximal airway identifies subsets of known airway cell types revealing details of the unique molecular pathogenesis of Cystic Fibrosis

Introduction/AbstractCystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts in excess of 70,000 people globally. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most significant determinant of morbidity and mortality. In this study we report results from a multi-institute consortium in which single cell transcriptomics were applied to define disease-related changes to the proximal airway of CF donors (n=19) undergoing transplantation for end-stage lung disease compared to the proximal airway of previously healthy lung donors (n=19). We found that all major airway epithelial cell types were conserved between control and CF donors. Disease-dependent differences were observed, including an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subtypes coupled with an unexpected decrease in cycling basal cells. This study developed a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.

cell biology↗

bioRxiv2019

Distributed dynamic coding for spatial working memory in hippocampal-prefrontal networks

Spatial working memory (SWM) is a central cognitive process during which the hippocampus and prefrontal cortex (PFC) encode and maintain spatial information for subsequent decision-making. This occurs in the context of ongoing computations relating to spatial position, recall of long-term memory, attention, amongst many others. To establish how intermittently presented information is integrated with ongoing computations we recorded single units, in both hippocampus and PFC, in control rats and those with a brain malformation during performance of a SWM task. Neurons that encode intermittent task parameters are also well-modulated in time and incorporated into a functional network across regions. Our results implicate a model in which ongoing oscillatory coordination among neurons in the hippocampal-PFC network defines a functional network that is poised to receive sensory inputs that are then integrated and multiplexed as working memory. These dynamics are systematically altered in disease and may provide potential targets for stimulation-based therapies.

neuroscience↗