Biology subjects

SHUTT, T.

Publications and source records attributed to SHUTT, T..

6 recordsLinked to original sources

bioRxiv2026

ACTIVATION OF THE ARYL HYDROCARBON RECEPTOR REDUCES VISCERAL HYPERSENSITIVITY IN A MOUSE MODEL OF COLITIS IN REMISSION

The aryl hydrocarbon receptor (AhR) is expressed on gut-projecting transient receptor potential vanilloid-1 (TRPV1)+ nociceptors, but whether it has a role in regulating abdominal pain remains to be determined. Approximately 50% of inflammatory bowel disease (IBD) patients experience chronic abdominal pain, even when their inflammatory disease is in remission. Previous work has shown that tryptophan metabolism to indole derivatives is reduced in IBD patients. Since microbial tryptophan metabolites (indole derivatives) serve as ligands for AhR, we hypothesized that reduced AhR activation contributes to enhanced pain sensitivity. We used a post-colitis mouse model of visceral hypersensitivity to examine the role of AhR as a mediator of nociception. AhR activation using both natural and synthetic agonists reduced visceral hypersensitivity in both male and female post-colitis mice. Conversely, pharmacological inhibition of AhR blocked the antinociceptive effects of indoles. Mechanistically, AhR activation by indole-3-pyruvic acid (IPyA) increased the transcription of the inward rectifying potassium channel Kir2.2, in TRPV1+ neurons and markedly reduced neuronal activation within the dorsal horn of the spinal cord. Metagenomic analysis revealed sex differences in indole-producing bacteria, with control males exhibiting enriched abundance of Akkermansia muciniphila and Alistipes compared to post-colitis males and female controls. These findings demonstrate that oral IPyA supplementation in post-colitis mice attenuates visceral hypersensitivity in part through activation of nociceptor AhR, providing insights that support the therapeutic targeting of AhR to treat abdominal pain in IBD patients in remission.

neuroscience↗

bioRxiv2026

Altered Steroidogenesis in Response to Impaired Mitochondrial Protein Homeostasis

Mitochondrial proteostasis is critical for organelle function, but how it influences mitochondrial steroidogenesis is not understood. We investigated the impact of impaired mitochondrial proteostasis on mitochondrial protein import and how this impacts cortisol production. We found that mild mitochondrial proteostatic stress increased cortisol synthesis whereas severe stress suppressed cortisol, revealing a biphasic steroidogenic response. Mild stress induced increases in cholesterol import and cortisol production in a manner dependent on STARD1-mediated cholesterol transport, which is the first and rate-limiting step in steroidogenesis. Severe stress reduced cortisol synthesis independently of STARD1 activity, indicating this inhibition occurs downstream in steroidogenesis. These findings reveal mitochondrial protein import as a regulatory node linking mitochondrial proteostasis to steroidogenic output. Furthermore, we observed increased cortisol synthesis in rotenone, A53T alpha-synuclein and PINK1-KO models of PD, suggesting that this response is relevant to PD-associated mitochondrial dysfunction. Together, our findings reveal a biphasic steroidogenic response to impairments in mitochondrial quality control with implications in human disease. Our work recognizes a previously unexplored branch of the mitochondrial stress response that enables cellular and physiological adaptations that can be detrimental if constitutively activated.

cell biology↗

bioRxiv2025

Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells

Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). These mutations disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR) - the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2-deficient cells. These results demonstrate the potential for pharmacologic HRI activation as a viable strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.

cell biology↗

bioRxiv2024

Validating the genus Pocheina (Acrasidae, Heterolobosea, Excavata) leads to the recognition of three major lineages within Acrasidae

Pocheina and Acrasis are two genera of heterolobosean sorocarpic amoebae within Acrasidae that have historically been considered close relatives. The two genera were differentiated based on their differing fruiting body morphologies. The validity of this taxonomic distinction was challenged when a SSU rRNA phylogenetic study placed an isolate morphologically identified as Pocheina rosea within a clade of Acrasis rosea isolates. The authors speculated that pocheinoid fruiting body morphology might be the result of aberrant A. rosea fruiting body development, which if true, would nullify this taxonomic distinction between genera. To clarify Acrasidae systematics, we analyzed SSU rRNA and ITS region sequences from multiple isolates of Pocheina, Acrasis, and Allovahlkampfia generated by PCR and transcriptomics. We demonstrate that the initial SSU sequence attributed to P. rosea originated from an A. rosea DNA contamination in its amplification reaction. Our analyses, based on morphology, SSU and 5.8S rRNA genes phylogenies, as well as comparative analyses of ITS1 and ITS2 sequences, resolve Acrasidae into three major lineages; Allovahlkampfia and the strongly supported clades comprising Pocheina and Acrasis. We confirm that the latter two genera can be identified by their fruiting body morphologies.

evolutionary biology↗

bioRxiv2022

The Ketogenic Diet Metabolite β-Hydroxybutyrate Promotes Mitochondrial Elongation via Deacetylation and Improves Autism-like Behavior in Zebrafish

The ketogenic diet (KD) is clinically beneficial and has therapeutic potential across a growing list of neurological disorders, including autism spectrum disorder (ASD). However, the underlying mechanisms mediating the benefits of the KD, which can also have undesirable side effects, remain undefined. To this end, improvements in mitochondrial morphology and function correlate with improved ASD behaviours in response to the KD, though how the KD influences mitochondrial morphology, and whether this is sufficient to improve behaviour remains unknown. Here, we investigate how beta-hydroxybutyrate (BHB), a key metabolite produced by the KD regulates mitochondrial morphology in HeLa cells, and whether this pathway could be exploited to alter phenotypes in a zebrafish model of ASD. We found that {beta}-oxidation of BHB promotes mitochondrial elongation in HeLa cells by increasing NAD+ levels, which in turn activates SIRT deacetylases that act on key regulators of both mitochondrial fusion and fission. Our data suggest that increasing NAD+ levels with its precursor, nicotinamide mononucleotide (NMN), is sufficient to promote mitochondrial hyperfusion. Finally, both BHB and NMN impact neurodevelopment in the shank3b+/- zebrafish model of ASD. Together, our findings elucidate a mechanism by which the ketogenic diet promotes mitochondrial elongation. Moreover, manipulation of this pathway may provide a novel avenue for the treatment of neurological disorders such as ASD that also may obviate potential complications of the KD in clinical practice.

molecular biology↗

bioRxiv2022

Potentiation of Adipogenesis by Reactive Oxygen Species is a Unifying Mechanism in the Pro-adipogenic Properties of Bisphenol A and its New Structural Analogues.

AimsStructural analogues of bisphenol A (BPA), including BPS and BPF, are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved. ResultsExposure to BPS, BPF, BPA or ROS generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation in adipose-derived progenitors isolated from mice. RNAseq analysis in BPS-exposed progenitors revealed modulation in pathways regulating adipogenesis and responses to oxidative stress. ROS was higher in bisphenol-exposed cells, while co-treatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondria membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher whole-body adiposity, as measured by TD-NMR, while postnatal exposure had no impact on adiposity in either sex. InnovationThese findings support existing evidence showing a role for ROS in regulating adipocyte differentiation and are the first to highlight ROS as a unifying mechanism that explains the pro-adipogenic properties of BPA and its structural analogues. ConclusionROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis.

molecular biology↗