Biology subjects

Fernandes, V.

Publications and source records attributed to Fernandes, V..

7 recordsLinked to original sources

bioRxiv2026

Acid sphingomyelinase inhibition restores RPE homeostasis and photoreceptor function in preclinical Stargardt macular degeneration models

Stargardt disease, which destroys central high-resolution vision in over 2 million people globally, lacks effective therapies. The primary site of damage in Stargardt disease is the retinal pigment epithelium (RPE), which safeguards photoreceptor health and function. Progressive loss of RPE integrity precedes visual deficits, yet insight into mechanisms driving RPE dysfunction and how this influences disease pathogenesis remains elusive. Here, we addressed this in cell-based and pigmented Abca4-/- Stargardt mice models using super-resolution imaging, bioinformatics, and biochemical approaches. We show that ceramide accumulation induced by bisretinoid-mediated overactivation of acid sphingomyelinase (ASM) in Abca4-/- RPE selectively disrupts Rab GTPases and ESCRT machinery involved in apical membrane trafficking and small extracellular vesicle (EV) biogenesis. Consequently, connexin 43 (Cx43) is misrouted from cell-cell junctions into EVs that are released apically by the RPE. This compromises RPE integrity and promotes subretinal immune cell recruitment, leading to photoreceptor dysfunction. Pharmacological ASM inhibition normalizes EV biogenesis and restores Cx43 localization. Decreasing RPE ceramide safeguards RPE structural integrity, limits subretinal microglia, and improves visual function in Abca4-/- mice. This study underscores the importance of the RPE as a communication hub in the retina and identifies ASM as a potential therapeutic target to prevent progressive vision loss.

neuroscience↗

bioRxiv2025

The ATO gene family governs Candida albicans colonisation in the dysbiotic gastrointestinal tract

The fungal pathogen Candida albicans colonises the human gut where short-chain fatty acids (SCFAs) offer sources of carbon. This fungus harbours one of the largest microbial families of ATO (Acetate Transport Ortholog) genes, which encode putative SCFA transport proteins. Here, we generate C. albicans null mutants lacking individual or all known putative SCFA transporter genes and compare their phenotypes in vitro and in vivo. We show that blocking ATO function in C. albicans impairs SCFA uptake and growth, particularly on acetate. The uptake of acetate is largely dependent on a functional Ato1 (also known as Frp3/Ato3) and it is effectively abolished upon deletion of all ATO genes. We further demonstrate that deletion of the entire ATO gene family, but not inactivation of ATO1 alone, compromises the stable colonisation of C. albicans in the murine gastrointestinal tract following bacterial disruption by broad-spectrum antibiotics. Our data suggest that the ATO gene family has expanded and diversified during the evolution of C. albicans to promote the fitness of this fungal commensal during gut colonisation, in part through SCFA utilisation. IMPORTANCEThe human gut is rich in microbial fermentation products such as SCFAs, which serve as key nutrients for both bacteria and fungi. C. albicans, a common fungal resident of the gut and a cause of opportunistic infections, carries an unusually large family of ATO genes. This study reveals that this ATO gene family is required for the efficient uptake of acetate, the most abundant SCFA in the gut, and for stable colonisation of the gut. These findings uncover a new layer of metabolic adaptation in fungal commensals of humans and suggest that transporter gene expansion can shape microbial fitness in response to environmental nutrient signals.

microbiology↗

bioRxiv2025

Expansion, functional diversification and gene fusion events in the Ato protein family

Candida albicans, a commensal opportunistic pathogen, exhibits remarkable metabolic flexibility and adaptability to environmental changes. In glucose-limited niches, it utilizes alternative carbon sources such as carboxylic acids, which may influence its pathogenicity. In Saccharomyces cerevisiae, the uptake of monocarboxylates occurs through regulated plasma membrane (PM) transport proteins, such as Ato1 (Ady2), which belongs to the Acetate Uptake Transporter (AceTr) family. In C. albicans, these proteins are notably expanded, consisting of ten Ato-like proteins (ATO1-ATO10), whose functions remain unknown. Here, we investigated the role of Ato proteins in carboxylic acid utilization by C. albicans using in-silico and functional analysis. Our data revealed that several C. albicans Atos retain conserved AceTr motifs but possess distinct structural features, including differences in pore radius and binding sites for acetate and lactate. Expression analysis revealed that Ato1, Ato2, Ato3, and Ato6 exhibit distinct cellular localization and expression levels on the plasma membrane, depending on the presence or absence of monocarboxylates. Remarkably, deletion of ATO1 impaired Ato2 and Ato3 expression and caused ER retention of a distinct form of Ato2, suggesting a central regulatory role for Ato1 in the Ato transport system. Finally, we identified a novel Ato-related protein family in vertebrates. This family has three consecutive 6-helix transport domains and a unique C-terminal fusion with Sua5/YciO/YrdC, an enzyme involved in tRNA modification. Overall, our data suggests that the Ato protein family might play a critical role in the utilization of acetic or lactic acids in C. albicans. It also proposes potential functional redundancy among its members, which may contribute to rapid environmental adaptation and pathogenicity.

microbiology↗

bioRxiv2024

Endocytosis of the plasma membrane carboxylate transporter Jen1 in Saccharomyces cerevisiae under alkali stress: a mechanism for preventing loss of essential metabolites

In batch cultures of Saccharomyces cerevisiae grown on lactate, medium alkalinization coincides with endocytosis of the Jen1 lactate/pyruvate transporter. To assess how culture pH impacts Jen1 endocytosis, S. cerevisiae was grown in carbon-limited continuous cultures with a mixed ethanol-lactate feed. When applying a linearly increasing pH (6.75 to 7.25), extracellular lactate and pyruvate concentrations increased progressively. Up to pH 7.0, these concentrations aligned with the thermodynamic equilibrium of Jen1-mediated electroneutral carboxylate-proton symport, while Jen1 internalization became more pronounced above pH 7.0. Transcriptional upregulation of genes involved in oxidative phosphorylation, together with higher residual lactate levels, indicated increased energy demands at supra-optimal pH values. By analyzing transport, endocytosis, and transcriptional responses in actively growing continuous cultures, this study uncovers pH-dependent physiological challenges associated with electroneutral carboxylate/proton symport. The data support the hypothesis that Jen1 internalization evolved to prevent intracellular metabolite loss under unfavorable pH conditions. These findings provide novel insights into the physiological consequences of transporter energy coupling and the ecophysiological relevance of anion transporters when extracellular pH approaches or exceeds cytosolic pH.

microbiology↗

bioRxiv2024

Scientific note on the potential beneficial effect of 1-octen-3-ol on the survival of Apis mellifera chronically exposed to low doses of fipronil.

Fipronil, a non-competitive antagonist of {gamma}-aminobutyric acid receptors (GABA-Rs), inhibits the flow of chloride ions in the nerve cells, leading to the insect death. In a previous work, the volatolome of bees chronically exposed to this insecticide (0.5 and 1 g/L) was analyzed and characterize the Apis mellifera metabolic responses. Two Volatile Organic Compounds or VOCs (1-octen-3-ol and 2,6-dimethylcyclohexanol) produced by bee were highlighted. We assumed that these VOCs could act as modulators of the GABA-R to counteract the effect of fipronil. The toxicity of these VOCs was tested on emerging bees for concentrations ranging from 0 to 3.4 g/L. Survival and the sucrose consumption were recorded during 21 days of chronic exposure. 1-octen-3-ol and 2,6-dimethylcyclohexanol did not significantly affect the proportion of survival at the end of the experiment, whatever their concentration. 1-octen-3-ol (0.5, 1, 1.7 and 3.4 g/L) was chosen to assess its effect in the case of co-exposure with fipronil (0.5 and 1 g/L). A beneficial effect on survival at 21 days was observed with an average improvement in survival rate for the co-exposed groups. This positive effect was not related to the VOC concentration and could be a direct effect (interaction with GABA-R) or a hormetic effect (global improvement of bee fitness).

pharmacology and toxicology↗

bioRxiv2022

Characterization of Arabian Peninsula whole exomes: exploring high inbreeding features

The exome (WES) capture enriched for UTRs on 90 Arabian Peninsula (AP) populations contributed nearly 20,000 new variants from a total over 145,000 total variants. Almost half of these variants were in UTR3, reflecting the low effort we have dedicated to cataloguing these regions, which can bear an important proportion of functional variants, as being discovered in genome-wide association studies. By applying several pathogenic predicting tools, we have demonstrated the high burden in potentially deleterious variants (especially in nonsynonymous and UTR variants located in genes that have been associated mainly with neurologic disease and congenital malformations) contained in AP WES, and the burden was as high as the consanguinity level (inferred as sum of runs of homozygosity, SROH) increased. Arabians had twice SROH values in relation to Europeans and East Asians, and within AP, Saudi Arabia had the highest values and Oman the lowest. We must pursuit cataloguing diversity in populations with high consanguinity, as the potentially pathogenic variants are not eliminated by genetic drift as much as in less consanguineous populations.

genetics↗

bioRxiv2021

Projecting ancient ancestry in modern-day Arabians and Iranians: a key role of the past exposed Arabo-Persian Gulf on human migrations

Arabian Peninsula is strategic for investigations centred on the structuring of the modern human population in the three main groups, in the awake of the out-of-Africa migration. Despite the poor climatic conditions for recovery of ancient DNA human evidence in Arabia, the availability of genomic data from neighbouring ancient specimens and of informative statistical tools allow better modelling the ancestry of these populations. We applied this approach to a dataset of 741,000 variants screened in 291 Arabians and 78 Iranians, and obtained insightful evidence. The west-east axis was a strong forcer of population structure in the Peninsula, and, more importantly, there were clear continuums throughout time linking west Arabia with Levant, and east Arabia with Iran and Caucasus. East Arabians also displayed the highest levels of the basal Eurasian lineage of all tested modern-day populations, a signal that was maintained even after correcting for possible bias due to recent sub-Saharan African input in their genomes. Not surprisingly, east Arabians were also the ones with higher similarity with Iberomaurusians, who were so far the best proxy for the basal Eurasians amongst the known ancient specimens. The basal Eurasian lineage is the signature of ancient non-Africans that diverged from the common European-East Asian pool before 50 thousand years ago, and before the later interbred with Neanderthals. Our results are strong evidence to include the exposed basin of the Arabo-Persian Gulf as possible home of basal Eurasians, to be investigated further on namely by searching ancient Arabian human specimens.

genetics↗