Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator PGC-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the PGC-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases.

Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca²⁺, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca²⁺, reduced OCR and ATP synthesis, and elevated ROS production. Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.

Down syndrome (DS), a complex disorder that is caused by the trisomy of chromosome 21 (Hsa21), is a major cause of congenital heart defects (CHD). Interestingly, only about 50% of individuals with Hsa21 trisomy manifest CHD. Here we review the genetic basis of CHD in DS, focusing on genes that regulate extracellular matrix (ECM) organization. The overexpression of Hsa21 genes likely underlies the molecular mechanisms that contribute to CHD, even though the genes responsible for CHD could only be located in a critical region of Hsa21. A role in causing CHD has been attributed not only to protein-coding Hsa21 genes, but also to genes on other chromosomes, as well as miRNAs and lncRNAs. It is likely that the contribution of more than one gene is required, and that the overexpression of Hsa21 genes acts in combination with other genetic events, such as specific mutations or polymorphisms, amplifying their effect. Moreover, a key function in determining alterations in cardiac morphogenesis might be played by ECM. A large number of genes encoding ECM proteins are overexpressed in trisomic human fetal hearts, and many of them appear to be under the control of a Hsa21 gene, the RUNX1 transcription factor.

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted Aβ in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the “typical” APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer’s disease.

We have carried out a retrospective study of chromosome anomalies associated with increased nuchal translucency (NT) in order to compare yield rates of karyotype, chromosome microarray analysis (CMA), and non-invasive prenatal testing (NIPT) in this condition. Presenting with increased NT or cystic hygroma ≥3.5 mm as an isolated sign, 249 fetuses underwent karyotype and/or CMA from 11 to 18 gestational weeks. Karyotype and fluorescence in situ hybridization (FISH) analyses detected 103 chromosomal anomalies including 95 aneuploidies and eight chromosomal rearrangements or derivatives. Further, seven pathogenic copy number variants (CNV), five likely pathogenic CNVs, and 15 variants of unknown significance (VOUS) were detected by CMA in fetuses with normal karyotype. Genetic testing is now facing new challenges due to results with uncertain clinical impacts. Additional investigations will be necessary to interpret these findings. More than 15% of the anomalies that we have diagnosed with invasive techniques could not be detected by NIPT. It is therefore definitely not recommended in the case of ultrasound anomalies. These results, while corroborating the use of CMA in fetuses with increased NT as a second tier after rapid aneuploidy testing, do not suggest a dismissal of karyotype analysis.

Background: Maternal nutrition represents a critical risk factor for adverse health outcomes in both mother and offspring. We aimed to investigate associations between maternal nutritional habits, biomarker status, and pregnancy outcome among Italian healthy normal-weight pregnancies. Methods: Multicenter prospective cohort study recruiting Italian healthy normal-weight women with singleton spontaneous pregnancies at 20 ± 2 weeks (T1) in Milan and Naples. All patients underwent nutritional evaluations by our collecting a 7-day weighed dietary record at 25 ± 1 weeks (T2) and a Food Frequency Questionnaire at 29 ± 2 weeks (T3). Maternal venous blood samples were collected at T3 to assess nutritional, inflammatory and oxidative biomarker concentrations (RBCs folate, vitamin D, hepcidin, total antioxidant capacity). Pregnancy outcomes were collected at delivery (T4). General linear models adjusted for confounding factors were estimated to investigate associations between maternal dietary pattern adherence, nutrient intakes, biomarker concentrations and delivery outcomes. Results: 219 healthy normal-weight pregnant women were enrolled. Vitamin D and RBCs folate concentrations, as well as micronutrient intakes, were consistently below the recommended range. In a multi-adjusted model, maternal adherence to the most prevalent ‘high meat, animal fats, grains’ dietary pattern was positively associated with hepcidin concentrations and negatively associated with gestational age at delivery in pregnancies carrying female fetuses. Hepcidin plasma levels were further negatively associated to placental weight, whereas vitamin D concentrations were positively associated to neonatal weight. Conclusions: A high adherence to an unbalanced ‘high meat, animal fats, grains’ pattern was detected among Italian normal-weight low-risk pregnancies, further associated with maternal pro-inflammatory status and gestational age at delivery. This evidence underlines the need for a dedicated nutritional counseling even among low-risk pregnancies.