Biology subjects

Diaz-Diaz, C.

Publications and source records attributed to Diaz-Diaz, C..

3 recordsLinked to original sources

bioRxiv2025

Mitochondria-Lysosomes Crosstalk Shapes Neonatal Metabolic Transition in Neonatal Enterocytes

The neonatal gastrointestinal tract mediates nutrient absorption and the establishment of immune tolerance to commensal microbiota. In early life, lysosome-rich enterocytes (LREs) in the ileum are necessary for the intracellular digestion of maternal milk proteins. However, the molecular mechanisms sustaining their function remain incompletely characterized. Here, we demonstrate that LRE mitochondrial homeostasis and autophagic capacity are critical for efficient nutrient uptake and maintenance of their specialized identity, as disruption of either process leads to premature differentiation into post-weaning enterocytes (PECs) with diminished endolysosomal and metabolic activity. Transcriptomic profiling further revealed that neonatal LREs exhibit a distinctive antioxidant signature, which preserves redox balance and safeguards the expression of the transcriptional regulators MAFB and BLIMP1, both central repressors of the neonatal-to-adult metabolic transition. These findings establish the mitochondria-lysosome axis as a key determinant of LRE function and neonatal metabolic programming. They also provide a mechanistic framework for understanding how organelle dysfunction and redox imbalance may contribute to early-life malnutrition syndromes, such as Kwashiorkor, and suggest therapeutic strategies aimed at preserving mitochondrial and lysosomal integrity.

developmental biology↗

bioRxiv2024

Activation of HIF2 leads to vascular remodeling and inflammation, coronary thrombosis and arterial dilation, recapitulating cardiac involvement of Kawasaki disease.

Backgroundglobal deletion of Vhl leads to vascular defects and early lethality, precluding the study of VHL/HIF signaling during coronary formation and homeostasis. Hypoxia pathway has been associated with cardiovascular diseases involving inflammation and vascular remodeling like atherosclerosis, but its role in Kawasaki Disease (KD) remains unknown. Coronary dilatation and vessel rupture are the most serious complications of KD, while the molecular mechanisms underlying these cardiac events remain poorly understood. Here we aim to determine the function of VHL/HIF pathway in the development of cardiovascular defects and its role in KD. MethodsWe generated a new mouse model to genetically hyperactivate hypoxia pathway in progenitors contributing to coronary vessels and cardiac fibroblasts (Vhl/Wt1). We characterized the model by means of echocardiography, magnetic resonance imaging, histological analysis and molecular approaches. Human cardiac tissue from KD individuals suffering fatal coronary aneurysm were screened for HIF signaling and inflammatory markers by immunohistochemistry. Resultsconditional Vhl KO do not undergo developmental abnormalities but displays cardiomegaly and epicardial vascular defects, with cardiac hypertrophy and progressive coronary diameter increase, as well as pericardial hemorrhage and systemic inflammation early after birth. Histological characterization reveals inflammation of coronary arteries, vascular remodeling with elastin breaks and dilatation, increased perivascular fibrosis and smooth muscle cells death, together with high incidence of intracoronary thrombus formation. In addition, the mutants display vascular calcification and severe cardiac inflammation and interstitial hemorrhages, dying suddenly between 15-20 weeks of age due to vessel rupture. Simultaneous elimination of HIF2 and VHL prevents the cardiovascular abnormalities displayed by single cVhl KO, highlighting the essential role of HIF2 in coronary instability and vascular inflammation. Histological characterization of human cardiac samples shows positive signal for HIF1 and specially HIF2, in the coronary lesions and its surroundings in regions with high inflammatory infiltration, confirming the activation of hypoxia signaling in KD patients with cardiovascular complications. ConclusionsOur data demonstrate the importance of HIF2 signaling in the development of coronary inflammation and vascular remodeling and provide new evidences connecting low oxygen tensions with cardiovascular lesions occurring during the onset of the most severe cases of KD. Furthermore, the Vhl/Wt1 mouse generated recapitulates cardiac features of KD with critical heart complications, providing a new platform to uncover unknown aspects of KD pathogenesis.

pathology↗

bioRxiv2023

P53 and BCL-2 family proteins PUMA and NOXA define competitive fitness in Pluripotent Cells

Cell Competition is a process by which neighboring cells compare their fitness. As a result, viable but suboptimal cells are selectively eliminated in the presence of fitter cells. In the early mammalian embryo, epiblast pluripotent cells undergo extensive Cell Competition, which prevents suboptimal cells from contributing to the newly forming organism. While competitive ability is regulated by MYC in the epiblast, the mechanisms that contribute to competitive fitness in this context are largely unknown. Here, we report that P53 and its pro-apoptotic targets PUMA and NOXA regulate apoptosis susceptibility and competitive fitness in pluripotent cells. PUMA is widely expressed specifically in pluripotent cells in vitro and in vivo. We show that the p53-PUMA/NOXA pathway regulates mitochondrial membrane potential and oxidative status. We found that P53 regulates MYC levels in pluripotent cells, which connects these two Cell competition pathways, however, MYC and PUMA/NOXA levels are independently regulated by P53. We propose a model that integrates a bifurcated P53 pathway regulating both MYC and PUMA/NOXA levels and determines competitive fitness through regulation of mitochondrial activity.

developmental biology↗