Biology subjects

Oregioni, A.

Publications and source records attributed to Oregioni, A..

4 recordsLinked to original sources

bioRxiv2026

Mitochondrial Optic Atrophy (OPA)1 expression regulates the injury response to neonatal hypoxia-ischaemia.

Neonatal hypoxic-ischaemic encephalopathy is a leading cause of mortality and long-term neurodevelopmental impairment, in which mitochondrial dysfunction is central to injury progression, yet the molecular mechanisms linking mitochondrial dynamics to neuropathology remain incompletely defined. We combined analysis of human developmental transcriptomic datasets with in vitro primary astrocyte models and an established neonatal mouse model of hypoxia-ischaemia (postnatal day 9, Rice-Vannucci model) to investigate the role of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). OPA1 expression and processing were assessed by quantitative PCR and western blotting, mitochondrial function by imaging and Seahorse bioenergetic assays, and mitochondrial DNA content by quantitative PCR in both astrocytes and whole-brain tissue following injury. Hypoxia-ischaemia induced rapid proteolytic processing of OPA1 in the neonatal brain and reduced OPA1 expression in astrocytes following oxygen-glucose deprivation. Genetic reduction of OPA1 in astrocytes resulted in mitochondrial fragmentation, impaired maximal respiration and spare respiratory capacity (p<0.05), and increased susceptibility to hypoxic stress (p<0.01). In vitro, OPA1 loss was associated with significant depletion of mitochondrial DNA (p<0.05), and mitochondrial DNA content was similarly reduced in the neonatal mouse brain 24 hours after hypoxia-ischaemia compared with controls (p<0.05). In contrast, OPA1 overexpression preserved mtDNA levels and significantly reduced in vivo brain tissue loss at 7 days after injury (p<0.05), while improving astrocyte survival following metabolic stress (p<0.001). These findings identify loss of mitochondrial DNA as a previously unrecognised component of mitochondrial pathology in neonatal hypoxic-ischaemic brain injury and demonstrate that OPA1 is a key determinant of mitochondrial integrity and bioenergetic resilience. Targeting OPA1-dependent pathways may represent a novel therapeutic strategy to limit brain injury following birth asphyxia.

neuroscience↗

bioRxiv2023

The Legionella collagen-like protein employs a unique binding mechanism for the recognition of host glycosaminoglycans

Bacterial adhesion is a fundamental process which enables colonisation of niche environments and is key for infection. However, in Legionella pneumophila, the causative agent of Legionnaires disease, these processes are not well understood. The Legionella collagen-like protein (Lcl) is an extracellular peripheral membrane protein that recognises sulphated glycosaminoglycans (GAGs) on the surface of eukaryotic cells, but also stimulates bacterial aggregation in response to divalent cations. Here we report the crystal structure of the Lcl C-terminal domain (Lcl-CTD) and present a model for intact Lcl. Our data reveal that Lcl-CTD forms an unusual dynamic trimer arrangement with a positively charged external surface and a negatively charged solvent exposed internal cavity. Through Molecular Dynamics (MD) simulations, we show how the GAG chondroitin-4-sulphate associates with the Lcl-CTD surface via unique binding modes. Our findings show that Lcl homologs are present across both the Pseudomonadota and Fibrobacterota-Chlorobiota-Bacteroidota phyla and suggest that Lcl may represent a versatile carbohydrate binding mechanism.

microbiology↗

bioRxiv2019

Functional characterisation of gut microbiota and metabolism in Type 2 diabetes indicates that Clostridiales and Enterococcus could play a key role in the disease

There is growing evidence indicating that gut microbiota contributes to the development of metabolic syndrome and Type 2 Diabetes (T2D). The most widely-used model for T2D research is the leptin deficient db/db mouse model. Yet, a characterisation of the gut microbial composition in this model in relationship with the metabolism is lacking. The objectives of this study were to identify metabolomics and microbial modulations associated with T2D in the db/db mouse model. The majority of microbial changes observed included an increase of Enterobacteriaceae and a decrease of Clostridiales in diabetics. The metabolomics interrogation of caecum indicated a lower proteolytic activity in diabetics, who also showed higher Short-Chain Fatty Acid (SCFA) levels. In the case of faeces, the model identified 9 metabolites, the main ones were acetate, butyrate and Branched Chain Amino Acids (BCAAs). Finally, liver was the organ with more metabolic links with gut-microbiota followed by the Gut-Brain Axis (GBA). In conclusion, the interaction between Clostridiales and Enterococcus with caecal metabolism could play a key role in the onset and development of diabetes. Further studies should investigate whether the role of these bacteria is causal or co-occurring.

microbiology↗

bioRxiv2018

A strategy to study intrinsically mixed folded proteins: The structure in solution of ataxin-3

It has increasingly become clear over the last two decades that proteins can contain both globular domains and intrinsically unfolded regions which both can contribute to function. While equally interesting, the disordered regions are difficult to study because they usually do not crystallize unless bound to partners and are not easily amenable to cryo-electron microscopy studies. Nuclear magnetic resonance spectroscopy remains the best technique to capture the structural features of intrinsically mixed folded proteins and describe their dynamics. These studies rely on the successful assignment of the spectrum, task not easy per se given the limited spread of the resonances of the disordered residues. Here, we describe assignment of the spectrum of ataxin-3, the protein responsible for the neurodegenerative Machado-Joseph disease. We used a 42 kDa construct containing a globular N-terminal josephin domain and a C-terminal tail which comprises thirteen polyglutamine repeats within a low-complexity region. We developed a strategy which allowed us to achieve 87% assignment of the spectrum. We show that the C-terminal tail is flexible with extended helical regions and interacts only marginally with the rest of the protein. We could also, for the first time, deduce the structure of the polyglutamine repeats within the context of the full-length protein and show that it has a strong helical propensity stabilized by the preceding region.

biophysics↗