Mitochondrial dysfunction is a hallmark of many diseases. The retrograde signaling initiated by dysfunctional mitochondria can bring about global changes in gene expression that alters cell ...morphology and function. Typically, this is attributed to disruption of important mitochondrial functions, such as ATP production, integration of metabolism, calcium homeostasis and regulation of apoptosis. Recent studies showed that in addition to these factors, mitochondrial dynamics might play an important role in stress signaling. Normal mitochondria are highly dynamic organelles whose size, shape and network are controlled by cell physiology. Defective mitochondrial dynamics play important roles in human diseases. Mitochondrial DNA defects and defective mitochondrial function have been reported in many cancers. Recent studies show that increased mitochondrial fission is a pro-tumorigenic phenotype. In this paper, we have explored the current understanding of the role of mitochondrial dynamics in pathologies. We present new data on mitochondrial dynamics and dysfunction to illustrate a causal link between mitochondrial DNA defects, excessive fission, mitochondrial retrograde signaling and cancer progression. 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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•Mitochondrial defects affecting Δμm induce stress signaling.•MtDNA depletion induces reorganization of actin cytoskeleton and regulates cell polarity.•MtDNA depletion induces mitochondrial fission and alters dynamics.•Inhibition of mitochondrial fission by Mdivi1 abrogates the acquired migratory potential of mtDNA depleted cells.•MtDNA depletion affects 3D organoid formation by primary esophageal epithelial cells.
Cytochrome c oxidase (CcO) is the terminal oxidase of the mitochondrial electron transport chain. This bigenomic enzyme in mammals contains 13 subunits of which the 3 catalytic subunits are encoded ...by the mitochondrial genes. The remaining 10 subunits with suspected roles in the regulation, and/or assembly, are coded by the nuclear genome. The enzyme contains two heme groups (heme a and a3) and two Cu2+ centers (Cu2+ A and Cu2+ B) as catalytic centers and handles more than 90% of molecular O2 respired by the mammalian cells and tissues. CcO is a highly regulated enzyme which is believed to be the pacesetter for mitochondrial oxidative metabolism and ATP synthesis. The structure and function of the enzyme are affected in a wide variety of diseases including cancer, neurodegenerative diseases, myocardial ischemia/reperfusion, bone and skeletal diseases, and diabetes. Despite handling a high O2 load the role of CcO in the production of reactive oxygen species still remains a subject of debate. However, a volume of evidence suggests that CcO dysfunction is invariably associated with increased mitochondrial reactive oxygen species production and cellular toxicity. In this paper we review the literature on mechanisms of multimodal regulation of CcO activity by a wide spectrum of physiological and pathological factors. We also review an array of literature on the direct or indirect roles of CcO in reactive oxygen species production.
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► Mammalian cytochrome oxidase (CcO) is a bigenomic enzyme with 13 subunits. ► The enzyme is regulated by subunit phosphorylation and allosteric effectors. ► CcO function is affected by hypoxia/ischemia, by drugs, and by alcohol. ► CcO function is also compromised in many diseases. ► CcO dysfunction often leads to increased production of reactive oxygen species.
Mitochondria play a central role not only in energy production but also in the integration of metabolic pathways as well as signals for apoptosis and autophagy. It is becoming increasingly apparent ...that mitochondria in mammalian cells play critical roles in the initiation and propagation of various signaling cascades. In particular, mitochondrial metabolic and respiratory states and status on mitochondrial genetic instability are communicated to the nucleus as an adaptive response through retrograde signaling. Each mammalian cell contains multiple copies of the mitochondrial genome (mtDNA). A reduction in mtDNA copy number has been reported in various human pathological conditions such as diabetes, obesity, neurodegenerative disorders, aging and cancer. Reduction in mtDNA copy number disrupts mitochondrial membrane potential (Δψm) resulting in dysfunctional mitochondria. Dysfunctional mitochondria trigger retrograde signaling and communicate their changing metabolic and functional state to the nucleus as an adaptive response resulting in an altered nuclear gene expression profile and altered cell physiology and morphology. In this review, we provide an overview of the various modes of mitochondrial retrograde signaling focusing particularly on the Ca(2+)/Calcineurin mediated retrograde signaling. We discuss the contribution of the key factors of the pathway such as Calcineurin, IGF1 receptor, Akt kinase and HnRNPA2 in the propagation of signaling and their role in modulating genetic and epigenetic changes favoring cellular reprogramming towards tumorigenesis.
Humidification dehumidification (HDH) desalination systems are well suited for small scale, off-grid desalination. These systems are very robust and can tolerate a wide range of feed salinities, ...making them a good candidate for treating produced water from hydraulically fractured natural gas wells. A primary engineering challenge for these systems is their high thermal energy consumption. In this study, we examine the use of multiple air extractions and injections to thermodynamically balance the HDH system, so as to make it more energy efficient. The effect of the number of extractions on several performance parameters is studied. In addition, we study the effect of the enthalpy pinch, which is a measure of performance for a heat and mass exchanger, on these performance parameters. Finally, we present results that can be used as guidelines in designing HDH systems. These results include the identification of appropriate temperatures for the extracted/injected air streams, the division of the heat duty between stages, and the value of the mass flow rate ratio in each stage at various values of enthalpy pinch.
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► GOR increases and recovery ratio decreases with decreasing cycle temperature range. ► Extraction (multi-staging) is only useful when heat and mass exchangers are large. ► Above a ...critical pinch there is no advantage to extraction (multi-staging).
Given simultaneous heat and mass transfer and a multiplicity of possible temperature and flow configurations, the optimization of humidification-dehumidification desalination systems is complex. In literature, this optimization has been tackled by considering moist air to follow the saturation curve in the humidifier and dehumidifier of a closed air water heated cycle. Under similar conditions and the same pinch point temperature differences, energy recovery was shown to improve with an increasing number of stages. In the present work, the limits upon the energy recovery and the water recovery (product water per unit of feed) of closed air water heated cycles are investigated. This is done by considering heat and mass exchangers to be sufficiently large to provide zero pinch point temperature and concentration differences with in the humidifier and dehumidifier. For cycles operating with a feed temperature of 25°C and a top air temperature of 70°C, GOR is limited to approximately 3.5 without extractions (i.e. single stage system) and 14 with a single extraction (i.e. dual stage system) while RR is limited to approximately 7% without extractions and 11% with a single extraction. GOR increases and RR decreases as the temperature range of the cycle decreases, i.e. as the feed temperature increases or the top air temperature decreases. A single extraction is shown to be useful only when heat and mass exchangers are large in size. In addition, the effects of salinity and the validity of ideal gas assumptions upon the modeling of HDH systems are discussed.
Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the β-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone ...mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the β-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.
World-wide water scarcity, especially in the developing world, indicates a pressing need to develop inexpensive, decentralized small-scale desalination technologies which use renewable resources of ...energy. This paper provides a comprehensive review of the state-of-the-art in one of the most promising of these technologies, solar-driven humidification–dehumidification (HDH) desalination. Previous studies have investigated many different variations on the HDH cycle. In this paper, performance parameters which enable comparison of the various versions of the HDH cycle have been defined and evaluated. To better compare these cycles, each has been represented in psychometric coordinates. The principal components of the HDH system are also reviewed and compared, including the humidifier, solar heaters, and dehumidifiers. Particular attention is given to solar air heaters, for which design data is limited; and direct air heating is compared to direct water heating in the cycle assessments. Alternative processes based on the HDH concept are also reviewed and compared. Further, novel proposals for improvement of the HDH cycle are outlined. It is concluded that HDH technology has great promise for decentralized small-scale water production applications, although additional research and development is needed for improving system efficiency and reducing capital cost.
We present light curves and classification spectra of 17 hydrogen-poor superluminous supernovae (SLSNe) from the Pan-STARRS1 Medium Deep Survey (PS1 MDS). Our sample contains all objects from the PS1 ...MDS sample with spectroscopic classification that are similar to either of the prototypes SN 2005ap or SN 2007bi, without an explicit limit on luminosity. With a redshift range , PS1 MDS is the first SLSN sample primarily probing the high-redshift population; our multifilter PS1 light curves probe the rest-frame UV emission, and hence the peak of the spectral energy distribution. We measure the temperature evolution and construct bolometric light curves, and find peak luminosities of erg s−1 and lower limits on the total radiated energies of erg. The light curve shapes are diverse, with both rise and decline times spanning a factor of ∼5 and several examples of double-peaked light curves. When correcting for the flux-limited nature of our survey, we find a median peak luminosity at 4000 of and a spread of .
Humidification dehumidification (HDH) is a promising technology for small-scale seawater desalination and has widespread application in drinking and industrial water treatment systems. This paper ...demonstrates the significance of a novel parameter known as the ‘modified heat capacity rate ratio’ (HCR) in the thermal design of HDH systems and in simultaneous heat and mass exchange (HME) devices. HCR is of particular importance in developing a fundamental understanding of the concept of thermodynamic balancing. A pilot-scale HDH unit (with a peak production capacity of 700l/day) has been constructed and detailed experiments have been performed on this unit. Based on these experiments, the recently developed theories behind the design of HDH systems with or without mass extraction and injection are validated. Furthermore, important concepts with regard to design and optimization of HME devices have been studied in the present experiments.
The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) ...and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP+) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O2•–) production by acting on complex I. In Raw264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O2•– and H2O2). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1α activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca2+/Cn pathway and is independent of ROS-induced HIF1α or AMPK pathways.
•Mitochondrial ROS (O2.•–, H2O2) induce a stress signaling pathway implicated in many diseases.•Mitochondrial ROS induce the Ca2+/Cn pathway in addition to HIF1α and AMPK pathways.•Mitochondria-targeted agents MitoPQ and MitoMet induce the Ca2+/Cn and AMPK pathways.•Inhibition of complex III by Antimycin A also activates the Ca2+/Cn and AMPK pathways but not HIF1α.•The three pathways appear to require different thresholds of mitochondrial ROS.
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