Biology subjects

Medeiros, I.

Publications and source records attributed to Medeiros, I..

3 recordsLinked to original sources

bioRxiv2024

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.

cell biology↗

bioRxiv2024

Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy

Alport syndrome (AS), caused by COL4A3,4,5 mutations, leads to progressive glomerular disease and eventual kidney failure. In Col43-/- mice (C57BL/6 background), we found that increased glomerular capillary deformability (reduced Youngs modulus, E) appears 2-3 months before detectable proteinuria or elevated serum creatinine. This early change indicates that podocyte injury precedes traditional clinical markers of disease and corresponds to reduced podocyte adhesion and loss. Bulk and podocyte-enriched RNA-seq data, obtained from deconvoluting bulk RNA sequencing data, showed that starting at 4 months, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) steadily rise while extracellular matrix remodeling, inflammation, epithelial-mesenchymal transition, and maladaptive repair begin. By 7 months, pathology shifts toward widespread parenchymal fibrosis, interleukin, cytokine, and chemokine signaling, cytoskeleton disruption, metabolic failure, and podocyte dedifferentiation. Notably, administration of the chemical chaperone Tauro-Urso-Deoxcycholic Acid (TUDCA) from weaning reduced ER stress, preserved glomerular stiffness, minimized podocyte detachment and loss, normalized inflammatory, injury, and fibrotic gene expression, and halved proteinuria and serum creatinine at 7 months, preserving kidney structure. Differentially expressed podocyte enriched genes from 4-month Col43-/- (vs WT) mice were mapped to human orthologs in the NEPTUNE cohort. Four genes (CRB2, GPC6, NKD1, STX11) were associated with End Stage Renal Disease or 40% loss of eGFR (ESRD40). Collectively, our results identify these four genes and ER stress/UPR as key and treatable drivers of podocyte injury and disease progression in Alport syndrome, well before overt proteinuria, and highlight UPR activation and several genes as promising targets for disease-modifying therapies.

cell biology↗

bioRxiv2023

Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways

Maternal Zika virus (ZIKV) infection during pregnancy can associate with severe intrauterine growth restriction (IUGR), placental damage, and metabolism disturbance, as well as newborn neurological abnormalities. Here, we investigated whether maternal ZIKV infection affects placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU-ZIKVPE243) and High (5x107 PFU-ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, for tissue collection at GD18.5 (term). Feto-placental growth of male fetuses was dramatically affected by ZIKV, whereas no differences were observed in female fetuses. ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose-6-phosphate in female placentas, with no differences in amino-acid transport potential. In contrast, glucose transport in male placentas was not affected by ZIKV, whilst a decreased placental protein expression of sodium-coupled neutral amino acid 2 (Snat2) was detected in the male low-dose ZIKV-infected group. There were also sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV infected pregnancies, showing that ZIKV can cause disturbance in the nutrient handling in the placental tissue. Our findings thus identify relevant molecular alterations in the placenta caused by maternal ZIKV infection related to nutrient transport and availability. Notably, our results suggest that female and male placentas adopt different strategies to cope with the altered metabolic state caused by ZIKV. This may have relevance for understanding the effects of congenital Zika syndrome and could potentially assist future therapeutic strategies. Author SummaryThe Zika virus (ZIKV) has emerged as a major global health concern in the past decade. ZIKV infection during pregnancy can cause infants to be born with microcephaly and fetal growth restriction, among other pregnancy complications. Currently, the number of cases of ZIKV disease declined onwards globally. However, transmission persists at low levels in several countries in the Americas and other endemic regions, with neither a licensed vaccine nor an antiviral drug available for prevention and treatment. Here, we use a mice model of maternal ZIKV infection to analyze placental nutrient transporters and nutrient-sensitive pathways as a potential link to the complications related to congenital ZIKV infection. We found that feto-placental growth of male fetuses was dramatically affected by ZIKV, whereas no differences were observed in female fetuses. We also found that placental nutrient transporters and nutrient-sensitive pathways were altered in response to ZIKV infection, depending on the fetal sex. Our study presents relevant molecular alterations caused by maternal ZIKV infection and suggests that female and male placentas adopt different strategies in response to the altered environment caused by ZIKV. Our observations may have relevance for understanding the effects of ZIKV infection and could potentially assist future therapeutic strategies.

physiology↗