Graphical Abstract Highlights d Mitochondrial ATP synthesis is reduced in Alzheimer's disease cell models d Lower mitochondrial Ca 2+ signal and pyruvate uptake impair cell bioenergetics d GSK-3b reduces HK1-mitochondria association, destabilizing MPC complexes d The defective mitochondrial pyruvate flux alters neuronal function SUMMARYMitochondria are key organelles for brain health. Mitochondrial alterations have been reported in several neurodegenerative disorders, including Alzheimer's disease (AD), and the comprehension of the underlying mechanisms appears crucial to understand their relationship with the pathology. Using multiple genetic, pharmacological, imaging, and biochemical approaches, we demonstrate that, in different familial AD cell models, mitochondrial ATP synthesis is affected. The defect depends on reduced mitochondrial pyruvate oxidation, due to both lower Ca 2+ -mediated stimulation of the Krebs cycle and dampened mitochondrial pyruvate uptake. Importantly, this latter event is linked to glycogen-synthase-kinase-3b (GSK-3b) hyper-activation, leading, in turn, to impaired recruitment of hexokinase 1 (HK1) to mitochondria, destabilization of mitochondrial-pyruvate-carrier (MPC) complexes, and decreased MPC2 protein levels. Remarkably, pharmacological GSK-3b inhibition in AD cells rescues MPC2 expression and improves mitochondrial ATP synthesis and respiration. The defective mitochondrial bioenergetics influences glutamate-induced neuronal excitotoxicity, thus representing a possible target for future therapeutic interventions. (A) Total cellular ATP levels (see STAR Methods) in control (pcDNA3) and PS2-T122R-expressing SH-SY5Y cells, grown either in glucose (Glu)-or galactose (Gal)containing medium. n = 42-90 wells from 4 independent experiments. (B) Representative images (YFP and CFP channels, left) and mean FRET % values (proportional to [ATP]) of nuclear (Nuc) and mitochondrial (Mit) ATeam1.03 probes in control, ER-b11-, PS2 WT-, PS2-T122R-, or PS2-N141I-expressing SH-SY5Y cells, grown in galactose-containing medium. n = 41-65 cells, 15-19 coverslips from 3 independent experiments. Scale bar, 10 mm. (C) Representative images and traces of ATP dynamics in primary cortical neurons of WT and PS2-N141I-tg mice (days in vitro [DIV] 6), transfected with both Nuc and Mit ATeam1.03. Where indicated, gramicidin (0.3 mM) was added. On the right, bars represent the mean decrease rate of Nuc-and Mit-ATP measured for 3 min, after 15 min from gramicidin addition (dotted boxes on traces). n = 30 cells, 24-26 coverslips from 3 independent experiments. Scale bar, 10 mm. (D) Left: representative traces of Ca 2+ dynamics measured with Fura-2 in primary hippocampal neurons of WT and PS2-N141I-tg mice (DIV 10-12), exposed to KCl. 20 min after KCl exposure, [Ca 2+ ] cyt recovery was evaluated, grouping cells for their 340/380 ratio (right; see STAR Methods). n = 3 independent experiments. (E) Left: representative traces of TMRM fluorescence measured in primary hippocampal neurons of WT and PS2-N141I-tg mice (DIV ...

Metabolic disorders are severe and chronic impairments of the health of many people and represent a challenge for the society as a whole that has to deal with an ever-increasing number of affected individuals. Among common metabolic disorders are Alzheimer’s disease, obesity, and type 2 diabetes. These disorders do not have a univocal genetic cause but rather can result from the interaction of multiple genes, lifestyle, and environmental factors. Mitochondrial alterations have emerged as a feature common to all these disorders, underlining perhaps an impaired coordination between cellular needs and mitochondrial responses that could contribute to their development and/or progression.

Pseudomyxoma Peritonei (PMP) is an anatomo-clinical condition characterized by the implantation of neoplastic cells on peritoneal surfaces with the production of a large amount of mucin. The rarity of the disease precludes the evaluation of treatment strategies within randomized controlled trials. Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has proven to be the only therapeutic option with potential chances of cure and long-term disease control. The present review discusses the epidemiology, pathogenesis, clinical presentation and treatment of PMP, focusing on the molecular factors involved in tumor progression and mucin production that could be used, in the upcoming future, to improve patient selection for surgery and to expand the therapeutic armamentarium.

The mechanisms by which neoplastic cells disseminate from the primary tumor to metastatic sites, so-called metastatic organotropism, remain poorly understood. Epithelial–mesenchymal transition (EMT) plays a role in cancer development and progression by converting static epithelial cells into the migratory and microenvironment-interacting mesenchymal cells, and by the modulation of chemoresistance and stemness of tumor cells. Several findings highlight that pathways involved in EMT and its reverse process (mesenchymal–epithelial transition, MET), now collectively called epithelial–mesenchymal plasticity (EMP), play a role in peritoneal metastases. So far, the relevance of factors linked to EMP in a unique peritoneal malignancy such as pseudomyxoma peritonei (PMP) has not been fully elucidated. In this review, we focus on the role of epithelial–mesenchymal dynamics in the metastatic process involving mucinous neoplastic dissemination in the peritoneum. In particular, we discuss the role of expression profiles and phenotypic transitions found in PMP in light of the recent concept of EMP. A better understanding of EMP-associated mechanisms driving peritoneal metastasis will help to provide a more targeted approach for PMP patients selected for locoregional interventions involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.