Biology subjects

Amaral, A. G.

Publications and source records attributed to Amaral, A. G..

4 recordsLinked to original sources

bioRxiv2026

Reproductive experience promotes permanent body growth independently of growth hormone

Pregnancy leads to many adaptations in the maternal body, some of which are reversible. However, reproductive experience can also result in permanent effects. Here, we investigated how pregnancy influences the somatotrophic system and the lasting effects of reproductive experience on the maternal organism. Reproductive experience induced a pronounced increase in lean body mass and longitudinal growth in both wild-type and growth hormone (GH)-deficient mice compared with age-matched virgins. Body growth was primarily observed during the first pregnancy, whereas a second gestation was mostly associated with increased adiposity. Increased GH secretion was observed in pregnant wild-type mice but not in pregnant GHRHR-deficient mice. Pregnancy-induced body growth is preserved despite disruption of GH-, ghrelin-, and estrogen-related signaling pathways. Data from a cohort of women with isolated GH deficiency (IGHD) caused by a loss-of-function mutation in the GHRHR gene revealed that nulliparous women were 7 cm shorter than those with one or more pregnancies. In conclusion, reproductive experience induces permanent changes in the maternal organism, promoting body growth in models that allow this response. Pregnancy-induced body growth appears to be independent of GH action. These findings underscore the need for further studies to investigate the long-lasting consequences of reproductive experience in females.

physiology↗

bioRxiv2025

Bclaf1 biomolecular condensates protect nuclear PTK2 from ubiquitin-proteasome system promoting cardiomyocyte survival during oxidative stress

PTK2, a non-receptor tyrosine kinase, plays a critical role in regulating essential cellular functions, including cell survival, by reducing p53 levels and activating the PI3K/AKT pathway. However, the mechanism underlying PTK2 stabilization during stress remains unclear. In this study, we identified Bclaf1, a multifunctional protein known to stabilize partners, as a PTK2 interactor. Using advanced microscopy techniques we identified nuclear Bclaf1 biomolecular condensates containing PTK2 in cardiomyocytes under oxidative stress. While diffuse PTK2 in the nucleus was susceptible to ubiquitination, PTK2 sequestered in the Bclaf1 condensates was protected from the ubiquitin-proteasome system (UPS). The K926 residue was identified as a ubiquitination site on PTK2, and subsequent proteasome inhibition experiments confirmed the role of the UPS in PTK2 homeostasis. Furthermore, disrupting Bclaf1 biomolecular condensates lead to PTK2 degradation, subsequently increasing p53 levels and activating apoptosis. Our findings support the role of Bclaf1 in the formation of pro-survival nuclear condensates that sequester and stabilize PTK2, promoting cardiomyocyte survival during oxidative stress. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/636487v3_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@15377a9org.highwire.dtl.DTLVardef@d5325forg.highwire.dtl.DTLVardef@de0ac9org.highwire.dtl.DTLVardef@196325d_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefMoretto et al. demonstrated that Bclaf1 undergo liquid-liquid phase separation (LLPS) during doxorubicin (Dox) induced oxidative stress to generate membraneless organelles where PTK2 is sequestered and protected from the ubiquitin-proteasome system (UPS). The maintenance of PTK2 stability may favor the p53 and Mdm2 interaction, which results in p53 ubiquitination and degradation, promoting cell survival. Loss of Bclaf1 disrupts PTK2 stabilization, leading to the ubiquitination and degradation of this kinase and downstream upregulation of p53, increasing cell death. HighlightsO_LIBclaf1 undergoes LLPS to stabilize protein partners during stress. C_LIO_LIPTK2 inside the Bclaf1 biomolecular condensates is protected from the UPS to promote cardiomyocyte survival during dox-induced oxidative stress. C_LIO_LIThe PTK2 ubiquitination site, lysine 926, was identified and the action of the UPS on PTK2 proteostasis was confirmed. C_LIO_LIBclaf1 knockdown results in overall protein ubiquitination and in PTK2 ubiquitination and degradation, resulting in increased levels of p53 and PUMA. C_LI

cell biology↗

bioRxiv2024

Pancreatic islets undergo functional and morphological adaptation during development of Barth Syndrome

Barth syndrome is a multisystem genetic disorder caused by mutation in TAFAZZIN, a gene that encodes a phospholipid:lysophospholipid transacylase important for cardiolipin remodeling. Barth Syndrome patients suffer from a number of symptoms including early heart failure, fatigue, and systemic metabolic alterations, including hypoglycemia. The endocrine pancreas is central to glucose homeostasis, however, the impact of defective cardiolipin remodeling on pancreatic islet function and the consequences for systemic metabolism is unclear. Surprisingly, in a mouse model with global TAFAZZIN knockdown, we observed improved glucose tolerance compared to wildtype littermates. We show that pancreatic islet metabolism and secretory function are robustly maintained through various compensatory mechanisms including increased glucose uptake and increased mitochondrial volume. Transcriptomics analyses revealed increased expression of genes encoding proteins involved in N-acetylglucosamine synthesis and protein O-linked N-acetylglucosaminylation. These pathways might provide a molecular mechanism for coupling metabolic changes to mitochondrial volume regulation.

physiology↗

bioRxiv2021

Regulation of Kidney Mitochondrial Function by Caloric Restriction

Caloric restriction (CR) prevents obesity, promotes healthy aging, and increases resilience against several pathological stimuli in laboratory rodents. At the mitochondrial level, protection promoted by CR in the brain and liver is related to higher calcium uptake rates and capacities, avoiding Ca2+-induced mitochondrial permeability transition. Dietary restriction has also been shown to increase kidney resistance against damaging stimuli such as ischemia/reperfusion, but if these effects are related to similar mitochondrial adaptations had not yet been uncovered. Here, we characterized changes in mitochondrial function in response to six months of CR in rats, measuring bioenergetic parameters, redox balance and calcium homeostasis. CR promoted an increase in mitochondrial oxygen consumption rates under non-phosphorylating and uncoupled conditions. While CR prevents mitochondrial reactive oxygen species production in many tissues, in kidney we found that mitochondrial H2O2 release was enhanced, although levels of carbonylated proteins and methionine sulfoxide were unchanged. Surprisingly, and opposite to the effects observed in brain and liver, mitochondria from CR animals are more prone to Ca2+-induced mitochondrial permeability transition. CR mitochondria also displayed higher calcium uptake rates, which were not accompanied by changes in calcium efflux rates, nor related to altered inner mitochondrial membrane potentials or the amounts of the mitochondrial calcium uniporter (MCU). Instead, increased mitochondrial calcium uptake rates in CR kidneys correlate with a loss of MICU2, an MCU modulator. Interestingly, MICU2 is also modulated by CR in liver, suggesting it has a broader diet-sensitive regulatory role controlling mitochondrial calcium homeostasis. Together, our results highlight the organ-specific bioenergetic, redox, and ionic transport effects of CR. Specifically, we describe the regulation of the expression of MICU2 and its effects on mitochondrial calcium transport as a novel and interesting aspect of the metabolic responses to dietary interventions.

biochemistry↗