The Mitochondrial Complex(I)ty of Cancer

Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH–ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pro-tumorigenic actions, involving different cellular signaling. Here, we discuss the role of Complex I in tumorigenesis, focusing on the specific participation of Complex I subunits in proliferation and metastasis of cancer cells

The true identity of the new world iguanid lizard liolaemus chillanensis Müller and Hellmich 1932 (Iguania: Liolaemidae) and description of a new species in the liolaemus elongatus group

Liolaemus is a particularly species-rich radiation of New World iguanid lizards from southern South America. Thanks to intense systematic and taxonomic research, the knowledge on its species-level diversity has increased rapidly over the past several years. The L. elongatus species-complex has received considerable attention and a remarkable case is Liolaemus chillanensis, a name that has been used for two different species that are sympatric in Termas de Chillán, central Chile. Since the holotype is lost, we propose that the first step to identify the true L. chillanensis is through the analysis of the original description. Then we provide a morphological and molecular characterization of L. chillanensis based on topotypes and a description of the taxon previously confused with it.Fil: Troncoso Palacios, Jaime. Universidad de Chile; ChileFil: Esquerré, Damien. The Australian National University; AustraliaFil: Urra, Félix A.. Universidad de Chile; ChileFil: Díaz, Hugo A.. Universidad de Chile; ChileFil: Castro Pastene, Carlos. Universidad de Concepción; ChileFil: Ruiz, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; Argentin

Description of the antipredatory head-wobble behaviour in Chilean rear-fanged snakes Tachymenis peruviana Wiegmann, 1835 and Tachymenis chilensis coronellina Werner, 1898 (Serpentes, Dipsadidae)

In this work, we describe the first records of head-wobble behaviour for Tachymenis peruviana and T. chilensis coronellina. We analyse this behaviour (occurrence, frequency) and accompanying displays in both species. Of particular note is that T. ch. coronellina exhibited more frequent head-wobbling than T. peruviana and, in both records, wind activity was observed during this antipredatory behaviour

The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD

Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function

Pictolysin-III, a Hemorrhagic Type-III Metalloproteinase Isolated from Bothrops pictus (Serpentes: Viperidae) Venom, Reduces Mitochondrial Respiration and Induces Cytokine Secretion in Epithelial and Stromal Cell Lines

From the venom of the Bothrops pictus snake, an endemic species from Peru, we recently have described toxins that inhibited platelet aggregation and cancer cell migration. In this work, we characterize a novel P-III class snake venom metalloproteinase, called pictolysin-III (Pic-III). It is a 62 kDa proteinase that hydrolyzes dimethyl casein, azocasein, gelatin, fibrinogen, and fibrin. The cations Mg2+ and Ca2+ enhanced its enzymatic activity, whereas Zn2+ inhibited it. In addition, EDTA and marimastat were also effective inhibitors. The amino acid sequence deduced from cDNA shows a multidomain structure that includes a proprotein, metalloproteinase, disintegrin-like, and cysteine-rich domains. Additionally, Pic-III reduces the convulxin- and thrombin-stimulated platelet aggregation and in vivo, it has hemorrhagic activity (DHM = 0.3 µg). In epithelial cell lines (MDA-MB-231 and Caco-2) and RMF-621 fibroblast, it triggers morphological changes that are accompanied by a decrease in mitochondrial respiration, glycolysis, and ATP levels, and an increase in NAD(P)H, mitochondrial ROS, and cytokine secretion. Moreover, Pic-III sensitizes to the cytotoxic BH3 mimetic drug ABT-199 (Venetoclax) in MDA-MB-231 cells. To our knowledge, Pic-III is the first SVMP reported with action on mitochondrial bioenergetics and may offer novel opportunities for promising lead compounds that inhibit platelet aggregation or ECM–cancer-cell interactions.</p

Targeting Metastasis with Snake Toxins: Molecular Mechanisms

Metastasis involves the migration of cancer cells from a primary tumor to invade and establish secondary tumors in distant organs, and it is the main cause for cancer-related deaths. Currently, the conventional cytostatic drugs target the proliferation of malignant cells, being ineffective in metastatic disease. This highlights the need to find new anti-metastatic drugs. Toxins isolated from snake venoms are a natural source of potentially useful molecular scaffolds to obtain agents with anti-migratory and anti-invasive effects in cancer cells. While there is greater evidence concerning the mechanisms of cell death induction of several snake toxin classes on cancer cells; only a reduced number of toxin classes have been reported on (i.e., disintegrins/disintegrin-like proteins, C-type lectin-like proteins, C-type lectins, serinproteases, cardiotoxins, snake venom cystatins) as inhibitors of adhesion, migration, and invasion of cancer cells. Here, we discuss the anti-metastatic mechanisms of snake toxins, distinguishing three targets, which involve (1) inhibition of extracellular matrix components-dependent adhesion and migration, (2) inhibition of epithelial-mesenchymal transition, and (3) inhibition of migration by alterations in the actin/cytoskeleton network

Regulation of mitochondrial function as a promising target in platelet activation-related diseases

© 2019 Elsevier Inc.Platelets are anucleated cell elements produced by fragmentation of the cytoplasm of megakaryocytes and have a unique metabolic phenotype compared with circulating leukocytes, exhibiting a high coupling efficiency to mitochondrial adenosine triphosphate production with reduced respiratory reserve capacity. Platelet mitochondria are well suited for ex vivo analysis of different diseases. Even some diseases induce mitochondrial changes in platelets without reflecting them in other organs. During platelet activation, an integrated participation of glycolysis and oxidative phosphorylation is mediated by oxidative stress production-dependent signaling. The platelet activation-dependent procoagulant activity mediated by collagen, thrombin and hyperglycemia induce mitochondrial dysfunction to promote thrombosis in oxidative stress-associated pathological conditions. Interestingly, some compounds exhibit a protective action on platelet mitochondrial dysfunction through con

The mitochondrial Complex(I)ty of cancer

© 2017 Urra, Muñoz, Lovy and Cárdenas. Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH-ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pr

Shedding Light on the Dentition and Venom Delivery System of the Rear-Fanged Snake, Galvarinus chilensis chilensis (Serpentes: Dipsadidae: Tachymenini) from Chile

Although the rear-fanged snake Galvarinus chilensis chilensis (formerly named Tachymenis ch. chilensis) causes ophidian accidents with clinical importance in Chile, the anatomical and histological characterizations of the venom delivery system (venom gland and fang) of this species still remain unknown. This study describes the dentition and characteristics of fangs and their ontogenetic variations in G. ch. chilensis. Moreover, histological and histochemistry analyses of the venom glands of this species are presented. Using micro-computed tomography and scanning electron microscopy, the dentitions of neonates, juveniles, and adults were analyzed, and no ontogenetic variations in teeth length and number present in the dentary and maxilla were observed. Moreover, we found three types of basic teeth, with distributional patterns conserved in all ontogenetic categories. The fangs exhibited a groove from the base to the middle. At the end of the groove, prominent ridges are formed. The fang and groove lengths were significantly distinct between ontogenetic categories. No differences between females and males were observed. Histologically, we found that the venom gland is close to the fangs and has a seromucous composition. Our results describe, for the first time, the distributional pattern and characteristics of the dentition and venom delivery system of the poorly studied snake G. ch. chilensis

The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD

Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function