Mitochondrial metabolism and cancer Porporato, Paolo Ettore; Filigheddu, Nicoletta; Pedro, José Manuel Bravo-San ...
Cell research,
03/2018, Volume:
28, Issue:
3
Journal Article
Peer reviewed
Open access
Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of ...powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioenergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents. However, tumors arise, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system, and many immunological functions rely on intact mitochondrial metabolism. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.
Autophagy is fundamental to the maintenance of intracellular homeostasis in virtually all human cells. Accordingly, defective autophagy predisposes healthy cells to undergoing malignant ...transformation. By contrast, malignant cells are able to harness autophagy to thrive, despite adverse microenvironmental conditions, and to resist therapeutic challenges. Thus, inhibition of autophagy has been proposed as a strategy to kill cancer cells or sensitize them to therapy; however, autophagy is also critical for optimal immune function, and mediates cell-extrinsic homeostatic effects owing to its central role in danger signalling by neoplastic cells responding to immunogenic chemotherapy and/or radiation therapy. In this Perspective, we discuss accumulating preclinical and clinical evidence in support of the all-too-often dismissed possibility that activating autophagy might be a relevant clinical objective that enables an increase in the effectiveness of immunogenic chemotherapy and/or radiation therapy.
Autophagy contributes to the maintenance of intracellular homeostasis in most cells of cardiovascular origin, including cardiomyocytes, endothelial cells, and arterial smooth muscle cells. Mitophagy ...is an autophagic response that specifically targets damaged, and hence potentially cytotoxic, mitochondria. As these organelles occupy a critical position in the bioenergetics of the cardiovascular system, mitophagy is particularly important for cardiovascular homeostasis in health and disease. Consistent with this notion, genetic defects in autophagy or mitophagy have been shown to exacerbate the propensity of laboratory animals to spontaneously develop cardiodegenerative disorders. Moreover, pharmacological or genetic maneuvers that alter the autophagic or mitophagic flux have been shown to influence disease outcome in rodent models of several cardiovascular conditions, such as myocardial infarction, various types of cardiomyopathy, and atherosclerosis. In this review, we discuss the intimate connection between autophagy, mitophagy, and cardiovascular disorders.
In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or ...acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate—or at least are compatible with—anticancer immune responses for long‐term tumor control.
Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many ...oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.
Autophagy has been described to have tumor‐suppressive as well as tumor‐promoting functions. This review discusses how stage and context alters the role for autophagy in cancer, and argues for further research prior to targeting autophagy in cancer therapy.
•A model predictive control approach is proposed for scheduling of CSP plants.•The most recent forecast and information about the plant state is used.•The generation schedule to which the plant has ...committed is conveniently tracked.•The generation schedule for the next trading day is produced.•The proposed approach is applied to a 50MW PTC based CSP plant with TES.
Thermal energy storage (TES) systems allow concentrated solar power (CSP) producers to participate in a day-ahead market. Therefore, the optimal power scheduling problem can be posed, whose objective is the maximization of profits derived from electricity sales. The daily generation schedule has to be offered in advance, usually the previous day before a certain time, thus an electricity price and weather forecast must be carried out. This paper proposes a model-based predictive control (MPC) approach for optimal scheduling in CSP plants. This approach has a dual purpose: (1) the periodic update of the generation schedule to track the schedule that has been committed to by means of the most recent electricity price and weather forecast and information about the plant state and (2) the generation of the optimal schedule for the next day. As these two tasks are related, they are performed simultaneously. Therefore, the MPC sliding window is composed of a first time interval to track the committed schedule and a second time interval to generate the next schedule for the following hours. This is then offered as the generation schedule for the next day at the appropriate time. The proposed approach is applied, in a simulation context, to a 50MW parabolic trough collector-based CSP plant with molten-salt-based TES. The chosen criterion to track the committed schedule is the even distribution of the possible generation error within the first interval. A case-study with overestimated initial DNI forecast is undertaken. The results show that the MPC control with short-term DNI forecast significantly improves the above-mentioned objective and allows for a reduction of the deviation from the scheduled generation, when compared with the case without short-term DNI forecast.
Recently, electrospun polymeric nanofibers have proven to be an interesting strategy for drug delivery systems application. The high surface-to-volume ratio of the fibers can improve some processes, ...such as cell binding and proliferation, drug loading, and mass transfer processes. One of the most important and studied areas of electrospinning is in the drug delivery field, for the controlled release of active substances ranging from antibiotics and anticancer agents to macromolecules such as proteins and DNA. The advantage of this method is that a wide variety of low solubility drugs can be loaded into the fibers to improve their bioavailability or to attain controlled release. This review presents an overview of the reported drugs loaded into polymeric nanofibers, to be used as drug delivery systems. For instance, it presents the reports on drugs with different bioactivities such as antiinflammatory, anti-microbial, anticancer, cardiovascular, anti-histamine, gastrointestinal, palliative and contraceptive drugs, etc. It also analyzes the electrospinning techniques used in each system, as well as the polymers used as matrices for the preparation of the nanofibers; unfolding the advantages of electrospun polymeric nanofibers over other drug delivery systems. This review intends to enlist and summarize the reported literature concerning this topic. In addition, it proposes future research in the field.
Autophagy in hepatic adaptation to stress Hazari, Younis; Bravo-San Pedro, José Manuel; Hetz, Claudio ...
Journal of hepatology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Volume:
72, Issue:
1
Journal Article
Peer reviewed
Open access
Autophagy is an evolutionarily ancient process whereby eukaryotic cells eliminate disposable or potentially dangerous cytoplasmic material, to support bioenergetic metabolism and adapt to stress. ...Accumulating evidence indicates that autophagy operates as a critical quality control mechanism for the maintenance of hepatic homeostasis in both parenchymal (hepatocytes) and non-parenchymal (stellate cells, sinusoidal endothelial cells, Kupffer cells) compartments. In line with this notion, insufficient autophagy has been aetiologically involved in the pathogenesis of multiple liver disorders, including alpha-1-antitrypsin deficiency, Wilson disease, non-alcoholic steatohepatitis, liver fibrosis and hepatocellular carcinoma. Here, we critically discuss the importance of functional autophagy for hepatic physiology, as well as the mechanisms whereby defects in autophagy cause liver disease.
Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant ...conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.
Organelle-specific initiation of cell death Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Kroemer, Guido
Nature cell biology,
08/2014, Volume:
16, Issue:
8
Journal Article
Peer reviewed
In a majority of pathophysiological settings, cell death is not accidental - it is controlled by a complex molecular apparatus. Such a system operates like a computer: it receives several inputs that ...inform on the current state of the cell and the extracellular microenvironment, integrates them and generates an output. Thus, depending on a network of signals generated at specific subcellular sites, cells can respond to stress by attemptinwg to recover homeostasis or by activating molecular cascades that lead to cell death by apoptosis or necrosis. Here, we discuss the mechanisms whereby cellular compartments - including the nucleus, mitochondria, plasma membrane, endoplasmic reticulum, Golgi apparatus, lysosomes, cytoskeleton and cytosol - sense homeostatic perturbations and translate them into a cell-death-initiating signal.
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