1,721,040 research outputs found
Mitochondrial dysfunctions in cancer and neurodegenerative disease
No full textMitochondria are dynamic, semi-autonomous organelles surrounded by a double membrane that have their own genome and protein synthesis machinery. In addition to being the major source of ATP in eukaryotes, they are the site of many important metabolic reactions such as the urea cycle, lipid metabolism, steroid hormone and porphyrin synthesis and interconversion of amino acids. Moreover, mitochondria play a central role in complex physiological processes including cellular proliferation, differentiation, apoptosis and in cellular processes like glucose sensing/insulin regulation and cellular Ca2+ homeostasis. It is therefore not surprising that mitochondrial dysfunctions have been found to be associated with several diseases such as neurodegenerative diseases, aging and cancer.
In this work, we investigate on the relationship between mitochondrial dynamics and two of the main research priorities in the world: cancer and neurodegenerative disease. In particular, we have addressed:
- i) The role of the PKCβ and mitochondrial physiology in the modulation of autophagy, a major phenomenon of cell biology, which acts as a pro-survival or pro-death mechanism and takes part in different biological events.
- ii) The identification of a microRNA (miR-25), highly expressed in cancer cells, that by targeting the newly discovered calcium channel of mitochondria (Mitochondrial Calcium Uniporter) reduces the sensitivity of cancer cells to apoptotic agents.
- iii) How, one of the most important cytokines for the aetiology of Multiple Sclerosis, TNFα, lead to alteration of the mitochondrial bioenergetics, with a consequent impairment of oligodendrocytes differentiation
In conclusion, these findings reveal new relations between mitochondria, calcium signalling and cell physiology, shedding new light on the role for this fascinating organelle
Mitophagy and Mitochondrial Balance
No full textMitochondria are highly dynamic organelles, with a morphology ranging from small roundish elements to large interconnected networks. This fine architecture has a significant impact on mitochondrial homeostasis, and mitochondrial morphology is highly connected to specific cellular process. Autophagy is a catabolic process in which cell constituents, including proteins and organelles, are delivered to the lysosomal compartment for degradation. Autophagy has multiple physiological functions and recent advances have demonstrated that this process is linked to different human diseases, such as cancer and neurodegenerative disorders. In particular, it has been found that autophagy is a key determinant for the life span of mitochondria through a particularly fine-tuned mechanism called mitophagy, a selective form of autophagy, which ensures the preservation of healthy mitochondria through the removal of damaged or superfluous mitochondria. Mitophagy has been found to be altered in several pathologies and aberrant or excessive levels of this process are found in common human disorders. Thus, the measurement of the mitophagy levels is of fundamental relevance to elucidate the molecular mechanism of this process and, most importantly, its role in cellular homeostasis and disease. In this review, we will provide an overview of the current methods used to measure mitophagic levels, with particular emphasis on the techniques based on fluorescent probes
The endoplasmic reticulum–mitochondria connection: One touch, multiple functions
No full textAbstractThe endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic “network structure” that facilitates the formation of interorganellar connections. The ER and mitochondria join together at multiple contact sites to form specific domains, termed mitochondria-ER associated membranes (MAMs), with distinct biochemical properties and a characteristic set of proteins. The functions of these two organelles are coordinated and executed at the ER–mitochondria interface, which provides a platform for the regulation of different processes. The roles played by the ER–mitochondria interface range from the coordination of calcium transfer to the regulation of mitochondrial fission and inflammasome formation as well as the provision of membranes for autophagy. The novel and unconventional processes that occur at the ER–mitochondria interface demonstrate its multifunctional and intrinsically dynamic nature. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components
Novel function of the tumor suppressor PML at ER-mitochondria sites in the control of autophagy
No full textAutophagy is a tightly regulated lysosomal
degradation process that mediates the sequestration of
intracellular entities to form autophagosomes, and their
delivery to lysosomes for bulk degradation
Endoplasmic reticulum-mitochondria Ca2+ crosstalk in the control of the tumor cell fate
No full textMitochondria-associated membranes are juxtaposed between the endoplasmic reticulum and mitochondria and have been identified as a critical hub in the regulation of apoptosis and tumor growth. One key function of mitochondria-associated membranes is to provide asylum to a number of proteins with tumor suppressor and oncogenic properties. In this review, we discuss how Ca2+ flux manipulation represents the primary mechanism underlying the action of several oncogenes and tumor-suppressor genes and how these networks might be manipulated to provide novel therapies for cancer. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech
H-Ras-driven tumoral maintenance is sustained through caveolin-1-dependent alterations in calcium signaling
No full textA growing body of research has highlighted the complex range of tumoral traits acquired during H-Ras-driven transformation and maintenance, which include proliferative signaling, growth suppressor evasion and resistance to cell death. Clear molecular information about these processes is not yet available, but recent evidence has provided solid support for the importance of mitochondria. Here, we show that the induction of oncogenic H-Ras leads to changes in intracellular calcium (Ca2+), evaluate the temporal relationship between oncogene expression and mitochondrial physiology, and demonstrate that Ca2+ homeostasis is altered by caveolin-1, a protein that has a key role in tumor maintenance. Our results indicate that tumor-suppressor caveolin-1 is a core component of the Ca2+-dependent apoptotic pathway and participates in the regulation of critical mitochondrial functions during tumor development. The compromised caveolin-1/Ca2+ axis contributes to failure in both mitochondrial metabolism and apoptosis, thereby sustaining the neoplastic phenotype. These results illustrate a direct link between Ca2+ regulation and mitochondrial biology in cance
Methods to monitor and compare mitochondrial and glycolytic ATP production.
No full textATP is commonly considered as the main energy unit of the cell and participates in a variety of cellular processes. Thus, intracellular ATP concentrations rapidly vary in response to a wide variety of stimuli, including nutrients, hormones, cytotoxic agents, and hypoxia. Such alterations not necessarily affect cytosolic and mitochondrial ATP to similar extents. From an oncological perspective, this is particularly relevant in the course of tumor progression as well as in the response of cancer cells to therapy. In normal cells, mitochondrial oxidative phosphorylation (OXPHOS) is the predominant source of ATP. Conversely, many cancer cells exhibit an increased flux through glycolysis irrespective of oxygen tension. Assessing the relative contribution of glycolysis and OXPHOS to intracellular ATP production is fundamental not only for obtaining further insights into the peculiarities and complexities of oncometabolism but also for developing therapeutic and diagnostic tools. Several techniques have been developed to measure intracellular ATP levels including enzymatic methods based on hexokinase, glucose-6-phosphate dehydrogenase, and firefly luciferase. Here, we summarize conventional methods for measuring intracellular ATP levels and we provide a detailed protocol based on cytosol- and mitochondrion-targeted variants of firefly luciferase to determine the relative contribution of glycolysis and OXPHOS to ATP synthesis
The inhibition of MDM2 slows cell proliferation and activates apoptosis in ADPKD cell lines
No full textIntroduction Autosomal dominant polycystic kidney disease (ADPKD) is characterised by progressive cysts formation and renal enlargement that in most of cases leads to end stage of renal disease (ESRD). This pathology is caused by mutations of either PKD1 or PKD2 genes that encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. These proteins function as receptor-channel complex able to regulate calcium homeostasis. PKD1/2 loss of function impairs different signalling pathways including cAMP and mTOR that are considered therapeutic targets for this disease. In fact, Tolvaptan, a vasopressin-2 antagonist that reduces cAMP levels, is the only drug approved for ADPKD treatment. Nevertheless, some ADPKD patients developed side effects in response to Tolvaptan including liver damage. Conversely, mTOR inhibitors that induced disease regression in ADPKD animal models failed the clinical trials. Results Here, we show that the inhibition of mTOR causes the activation of autophagy in ADPKD cells that could reduce therapy effectiveness by drug degradation through the autophagic vesicles. Consistently, the combined treatment with rapamycin and chloroquine, an autophagy inhibitor, potentiates the decrease of cell proliferation induced by rapamycin. To overcome the dangerous activation of autophagy by mTOR inhibition, we targeted MDM2 (a downstream effector of mTOR signalling) that is involved in TP53 degradation by using RG7112, a small-molecule MDM2 inhibitor used for the treatment of haematologic malignancies. The inhibition of MDM2 by RG7112 prevents TP53 degradation and increases p21 expression leading to the decrease of cell proliferation and the activation of apoptosis. Conclusion The targeting of MDM2 by RG7112 might represent a new therapeutic option for the treatment of ADPKD
Calcium Dynamics as a Machine for Decoding Signals
No full textCalcium (Ca2+) is considered one of the most-important biological cations, because it is implicated in cell physiopathology and cell fate through a finely tuned signaling system. In support of this notion, Ca2+is the primary driver of cell proliferation and cell growth; however, it is also intimately linked to cell death. Functional abnormalities or mutations in proteins that mediate Ca2+homeostasis usually lead to a plethora of diseases and pathogenic states, including cancer, heart failure, diabetes, and neurodegenerative disease. In this review, we examine recent discoveries in the highly localized nature of Ca2+-dependent signal transduction and its roles in cell fate, inflammasome activation, and synaptic transmission
Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs)
No full textUntil 1972, the term ‘apoptosis’ was used to differentiate the programmed cell death that naturally occurs in organismal development from the acute tissue death referred to as necrosis. Many studies on cell death and programmed cell death have been published and most are, at least to some degree, related to cancer. Some key proteins and molecular pathways implicated in cell death have been analyzed, whereas others are still being actively researched; therefore, an increasing number of cellular compartments and organelles are being implicated in cell death and cancer. Here, we discuss the mitochondria and subdomains of the endoplasmic reticulum (ER) that interact with mitochondria, the mitochondria-associated membranes (MAMs), which have been identified as critical hubs in the regulation of cell death and tumor growth. MAMs-dependent calcium (Ca2+) release from the ER allows selective Ca2+ uptake by the mitochondria. The perturbation of Ca2+ homeostasis in cancer cells is correlated with sustained cell proliferation and the inhibition of cell death through the modulation of Ca2+ signaling. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux
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