Biology subjects

Martino, D.

Publications and source records attributed to Martino, D..

7 recordsLinked to original sources

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↗

bioRxiv2023

The influence of prenatal alcohol exposure and maternal diet on offspring DNA methylation: a cross-species study

Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in new-born pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.

genetics↗

bioRxiv2023

Fathers' preconception smoking and offspring DNA methylation: A two generation study

RationaleExperimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are however limited. We aim to identify epigenetic marks in offspring associated with fathers preconception smoking. MethodsWe conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort on fathers any preconception smoking (N=875 offspring) and fathers pubertal onset smoking <15 years (N=304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, maternal smoking and personal smoking. EWAS of maternal and offspring personal smoking were performed for replication. ResultsFathers smoking commencing preconception was associated with methylation of blood DNA in offspring at two Cytosine-phosphate-Guanine sites (CpGs) (False Discovery Rate (FDR) <0.05) in PRR5 and CENPP. Fathers pubertal onset smoking was associated with 19 CpGs (FDR <0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (P< 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. ConclusionFathers preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underly epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.

genomics↗

bioRxiv2021

Early-life respiratory viral infection results in impairment of adult lung function

Respiratory viral infections in early-life are linked to the development of chronic lung diseases that persist into adulthood. The aim of this study was to develop a mouse model of early-life respiratory viral infection that would lead to impaired lung function in adulthood. BALB/c pups were infected at seven days of life with one of the following respiratory viruses: influenza A/Mem/1/71 "M71", influenza A/Puerto Rico/8/34 "PR8" or attenuated mengovirus "Mengo". Lung function and airways responsiveness (AHR) to methacholine were assessed seven weeks later, using the forced oscillation technique, and data were compared between male and female mice. PR8 infection was associated with significantly increased responsiveness to methacholine (for airway resistance, tissue damping, tissue elastance and hystersivity) for both sexes. M71 infection resulted in less severe responses especially in adult males. Early-life Mengo infection led to significantly higher responsiveness to MCh for males only (for airway resistance and tissue damping), suggesting sex dependant effects in lung function parameters measured. In summary, we have established a murine model where respiratory viral infection on day seven of life leads to AHR in adulthood. Importantly, the model recapitulates key variations in susceptibility related to sex and nature of viral pathogen that have previously been observed in human epidemiological studies. Our findings reveal new insights into the early origins of AHR and provide a tractable model system for future studies to unlock the mechanisms that determine pathogenesis.

immunology↗

bioRxiv2021

Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells

Children typically experience more mild symptoms of COVID-19 when compared to adults. There is a strong body of evidence that children are also less susceptible to SARS-CoV-2 infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remains to be determined. Here, we use primary nasal epithelial cells from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the nasal epithelial cells of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the nasal epithelial cells of children. Importantly, the Delta variant also replicated to significantly lower titres in the nasal epithelial cells of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.

microbiology↗

bioRxiv2021

Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss

Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Here, we describe a novel homozygous MFN2 variant, D414V, in a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy. Characterization of patient fibroblasts reveals phenotypes consistent with impaired MFN2 functions and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

genetics↗

bioRxiv2020

Mapping the landscape of chromatin dynamics during naïve CD4+ T-cell activation.

T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and ultimately cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naive CD4+ T-cells. Using a well-established ex vivo protocol of canonical T-cell receptor signaling, we generated genome-wide chromatin maps of naive T-cells from pediatric donors in quiescent or recently activated states. We identified thousands of individual chromatin accessibility peaks that are associated with T-cell activation. The majority of these were localized to intronic and intergenic enhancer regions, marked by active histone modifications whilst quiescence was maintained by repressive histone marks. Regions of activation-associated gains in chromatin accessibility were enriched for well-known pioneer transcription factor motifs, and super-enhancer regions associated with distinct gene regulatory networks. These cis-regulatory elements together brought about distinct transcriptional signatures in activated cells including TNFa-NFkB signaling, hormone-responsive genes, inflammatory response genes and IL2-STAT5 signaling. Our data provides novel insights into the chromatin dynamics and motif usage of T-cell receptor signaling events in early life. The characterized pathways demonstrate the utility of chromatin profiling techniques applied to bio-banked samples for characterizing gene regulatory elements.

immunology↗