Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target

Glaucoma is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with age and the level of intraocular pressure (IOP). IOP reduction is currently the only therapeutic modality shown to slow glaucoma progression. However, patients still lose vision despite best treatment, suggesting that other factors confer susceptibility. Several studies indicate that mitochondrial function may underlie both susceptibility and resistance to developing glaucoma. Mitochondria meet high energy demand, in the form of ATP, that is required for the maintenance of optimum retinal ganglion cell (RGC) function. Reduced nicotinamide adenine dinucleotide (NAD+) levels have been closely correlated to mitochondrial dysfunction and have been implicated in several neurodegenerative diseases including glaucoma. NAD+ is at the centre of various metabolic reactions culminating in ATP production—essential for RGC function. In this review we present various pathways that influence the NAD+(H) redox state, affecting mitochondrial function and making RGCs susceptible to degeneration. Such disruptions of the NAD+(H) redox state are generalised and not solely induced in RGCs because of high IOP. This places the NAD+(H) redox state as a potential systemic biomarker for glaucoma susceptibility and progression; a hypothesis which may be tested in clinical trials and then translated to clinical practice.

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ATM is activated by ATP depletion and modulates mitochondrial function through NRF1

10.1101/414490 ◽

2018 ◽

Author(s):

Hei-Man Chow ◽

Aifang Cheng ◽

Xuan Song ◽

Mavis R. Swerdel ◽

Ronald P. Hart ◽

...

Keyword(s):

Purkinje Cells ◽

Mitochondrial Function ◽

Energy Demand ◽

Nuclear Translocation ◽

Physiological Activity ◽

Mitochondrial Gene ◽

High Energy ◽

Atp Depletion ◽

Nuclear Respiratory Factor ◽

Atp Levels

AbstractWe have uncovered new insights into the symptoms of ataxia-telangiectasia (A-T). Neurons with high physiological activity, particularly cerebellar Purkinje cells, have large and dynamic ATP demands. Depletion of ATP generates reactive oxygen species that activate ATM (the A-T Mutated gene product). Activated in this way, but not by DNA damage, ATM phosphorylates nuclear respiratory factor-1 (NRF1). This leads to NRF1 dimerization, nuclear translocation and the upregulation of nuclear-encoded mitochondrial genes, thus enhancing the capacity of the electron transport chain (ETC) and restoring mitochondrial function. In cells with ATM deficiency, resting ATP levels are normal, but cells replenish ATP poorly following surges in energy demand and chronic ATP insufficiency endangers cell survival. This is a particular problem for energy-intensive cells such as Purkinje cells, which degenerate in A-T. Our findings thus identify ATM as a guardian of mitochondrial output as well as genomic integrity, and suggest that alternate fuel sources may ameliorate A-T disease symptoms.SummaryOxidative stress, resulting from neuronal activity and depleted ATP levels, activates ATM, which phosphorylates NRF1, causing nuclear translocation and upregulation of mitochondrial gene expression. In ATM deficiency, ATP levels recover more slowly, particularly in active neurons with high energy demands.

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Metabolic Flexibility and Mitochondrial Bioenergetics in the Failing Heart. Therapeutic Approaches

Romanian Journal of Cardiology ◽

10.47803/rjc.2021.31.2.269 ◽

2021 ◽

Vol 31 (2) ◽

pp. 269-282

Author(s):

Mariana G. ROSCA

Keyword(s):

Energy Demand ◽

Ketone Bodies ◽

Critical Role ◽

Redox Status ◽

High Energy ◽

Energy Deficit ◽

Metabolic Flexibility ◽

Therapeutic Approaches ◽

Atp Production ◽

Reduced Ejection Fraction

Objectives. We will review current concepts regarding bioenergetic decline in heart failure (HF). In the heart, the high energy demand must be met by continuous ATP generation. Cardiac energetic machinery orchestrates the ATP production by using oxidation of multiple energetic substrates including fatty acids (FA), glucose, amino acids and ketone bodies. The normal heart is metabolically flexible and able to use different energetic fuels during physiologic or pathologic circumstances to better match the energy demand. Mitochondria have critical role in maintaining cardiac metabolic flexibility. Methods. We analyzed the scientific literature pertinent to HF and mitochondrial dysfunction. Results. The general consent is that metabolic fl exibility is lost in HF with either preserved or reduced ejection fraction (HFpEF and HFrEF, respectively). The prototype of HFpEF is the metabolic heart disease that is characterized by increased reliance on FA oxidation for ATP production and decreased glucose oxidation, while HFrEF presents a decreased FA oxidation. Both types of HF are associated with a decline in mitochondrial function leading to increased oxidative stress, abnormalities in the redox status and energy deficit. Conclusion. Current research is committed to find novel metabolically targeted therapeutic approaches to improve energetic metabolism and alleviate HF progression.

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Metabolic Remodeling and Implicated Calcium and Signal Transduction Pathways in the Pathogenesis of Heart Failure

International Journal of Molecular Sciences ◽

10.3390/ijms221910579 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10579

Author(s):

Antoine H. Chaanine

Keyword(s):

Heart Failure ◽

Signaling Pathways ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

High Energy ◽

Atp Production ◽

Cellular Survival ◽

Energy Demands ◽

Metabolic Remodeling ◽

Close Proximity

The heart is an organ with high-energy demands in which the mitochondria are most abundant. They are considered the powerhouse of the cell and occupy a central role in cellular metabolism. The intermyofibrillar mitochondria constitute the majority of the three-mitochondrial subpopulations in the heart. They are also considered to be the most important in terms of their ability to participate in calcium and cellular signaling, which are critical for the regulation of mitochondrial function and adenosine triphosphate (ATP) production. This is because they are located in very close proximity with the endoplasmic reticulum (ER), and for the presence of tethering complexes enabling interorganelle crosstalk via calcium signaling. Calcium is an important second messenger that regulates mitochondrial function. It promotes ATP production and cellular survival under physiological changes in cardiac energetic demand. This is accomplished in concert with signaling pathways that regulate both calcium cycling and mitochondrial function. Perturbations in mitochondrial homeostasis and metabolic remodeling occupy a central role in the pathogenesis of heart failure. In this review we will discuss perturbations in ER-mitochondrial crosstalk and touch on important signaling pathways and molecular mechanisms involved in the dysregulation of calcium homeostasis and mitochondrial function in heart failure.

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Cardiac mitochondrial function depends on BUD23 mediated ribosome programming

eLife ◽

10.7554/elife.50705 ◽

2020 ◽

Vol 9 ◽

Author(s):

Matthew Baxter ◽

Maria Voronkov ◽

Toryn Poolman ◽

Gina Galli ◽

Christian Pinali ◽

...

Keyword(s):

Mitochondrial Function ◽

Energy Demand ◽

Critical Role ◽

A549 Cells ◽

Gc Content ◽

High Energy ◽

Mouse Development ◽

Mitochondrial Content ◽

And Function ◽

External Stimuli

Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells. Deletion of Bud23 in murine cardiomyocytes reduced mitochondrial content and function, leading to severe cardiomyopathy and death. We discovered that BUD23 selectively promotes ribosomal interaction with low GC-content 5’UTRs. Taken together we identify a critical role for BUD23 in bioenergetics gene expression, by promoting efficient translation of mRNA transcripts with low 5’UTR GC content. BUD23 emerges as essential to mouse development, and to postnatal cardiac function.

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Changes in lipid peroxidation during pregnancy and after delivery in rats: effect of pinealectomy

Reproduction ◽

10.1530/reprod/119.1.143 ◽

2000 ◽

pp. 143-149 ◽

Cited By ~ 9

Author(s):

RM Sainz ◽

RJ Reiter ◽

JC Mayo ◽

J Cabrera ◽

DX Tan ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Oxidative Damage ◽

Energy Demand ◽

Physiological State ◽

High Energy ◽

Free Radical Scavengers ◽

Radical Scavengers ◽

Oxygen Requirement ◽

Pregnant Rats

Pregnancy is a physiological state accompanied by a high energy demand of many bodily functions and an increased oxygen requirement. Because of the increased intake and utilization of oxygen, increased levels of oxidative stress would be expected. In the present study, the degree of lipid peroxidation was examined in different tissues from non-pregnant and pregnant rats after the delivery of their young. Melatonin and other indole metabolites are known to be direct free radical scavengers and indirect antioxidants. Thus the effect of pinealectomy at 1 month before pregnancy on the accumulation of lipid damage was investigated in non-pregnant and pregnant rats after the delivery of their young. Malonaldehyde and 4-hydroxyalkenal concentrations were measured in the lung, uterus, liver, brain, kidney, thymus and spleen from intact and pinealectomized pregnant rats soon after birth of their young and at 14 and 21 days after delivery. The same parameters were also evaluated in intact and pinealectomized non-pregnant rats. Shortly after delivery, lipid oxidative damage was increased in lung, uterus, brain, kidney and thymus of the mothers. No differences were detected in liver and spleen. Pinealectomy enhanced this effect in the uterus and lung. It is concluded that during pregnancy high levels of oxidative stress induce an increase in oxidative damage to lipids, which in some cases is inhibited by the antioxidative actions of pineal indoles.

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The Quorum Sensing Auto-Inducer 2 (AI-2) Stimulates Nitrogen Fixation and Favors Ethanol Production over Biomass Accumulation in Zymomonas mobilis

International Journal of Molecular Sciences ◽

10.3390/ijms22115628 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5628

Author(s):

Valquíria Campos Alencar ◽

Juliana de Fátima dos Santos Silva ◽

Renata Ozelami Vilas Boas ◽

Vinícius Manganaro Farnézio ◽

Yara N. L. F. de Maria ◽

...

Keyword(s):

Nitrogen Fixation ◽

Quorum Sensing ◽

Ethanol Production ◽

N2 Fixation ◽

Energy Demand ◽

Zymomonas Mobilis ◽

Biomass Accumulation ◽

High Energy ◽

Gram Negative ◽

Expression Of Genes

Autoinducer 2 (or AI-2) is one of the molecules used by bacteria to trigger the Quorum Sensing (QS) response, which activates expression of genes involved in a series of alternative mechanisms, when cells reach high population densities (including bioluminescence, motility, biofilm formation, stress resistance, and production of public goods, or pathogenicity factors, among others). Contrary to most autoinducers, AI-2 can induce QS responses in both Gram-negative and Gram-positive bacteria, and has been suggested to constitute a trans-specific system of bacterial communication, capable of affecting even bacteria that cannot produce this autoinducer. In this work, we demonstrate that the ethanologenic Gram-negative bacterium Zymomonas mobilis (a non-AI-2 producer) responds to exogenous AI-2 by modulating expression of genes involved in mechanisms typically associated with QS in other bacteria, such as motility, DNA repair, and nitrogen fixation. Interestingly, the metabolism of AI-2-induced Z. mobilis cells seems to favor ethanol production over biomass accumulation, probably as an adaptation to the high-energy demand of N2 fixation. This opens the possibility of employing AI-2 during the industrial production of second-generation ethanol, as a way to boost N2 fixation by these bacteria, which could reduce costs associated with the use of nitrogen-based fertilizers, without compromising ethanol production in industrial plants.

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IoT Platform for Energy Sustainability in University Campuses

Sensors ◽

10.3390/s21020357 ◽

2021 ◽

Vol 21 (2) ◽

pp. 357

Author(s):

Pedro Moura ◽

José Ignacio Moreno ◽

Gregorio López López ◽

Manuel Alvarez-Campana

Keyword(s):

Energy Demand ◽

New Technologies ◽

Low Cost ◽

Sustainable Use ◽

High Energy ◽

Appropriate Technology ◽

Monitoring And Control ◽

Energy Sustainability ◽

University Campuses ◽

Iot Platform

University campuses are normally constituted of large buildings responsible for high energy demand, and are also important as demonstration sites for new technologies and systems. This paper presents the results of achieving energy sustainability in a testbed composed of a set of four buildings that constitute the Telecommunications Engineering School of the Universidad Politécnica de Madrid. In the paper, after characterizing the consumption of university buildings for a complete year, different options to achieve more sustainable use of energy are presented, considering the integration of renewable generation sources, namely photovoltaic generation, and monitoring and controlling electricity demand. To ensure the implementation of the desired monitoring and control, an internet of things (IoT) platform based on wireless sensor network (WSN) infrastructure was designed and installed. Such a platform supports a smart system to control the heating, ventilation, and air conditioning (HVAC) and lighting systems in buildings. Furthermore, the paper presents the developed IoT-based platform, as well as the implemented services. As a result, the paper illustrates how providing old existing buildings with the appropriate technology can contribute to the objective of transforming such buildings into nearly zero-energy buildings (nZEB) at a low cost.

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Early alterations of neurovascular unit in the retina in mouse models of tauopathy

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01149-y ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Fan Xia ◽

Yonju Ha ◽

Shuizhen Shi ◽

Yi Li ◽

Shengguo Li ◽

...

Keyword(s):

Transgenic Mice ◽

Mouse Models ◽

Molecular Mechanisms ◽

Early Stage ◽

Leukocyte Adhesion ◽

Neurovascular Unit ◽

Integrated Analysis ◽

Therapeutic Effects ◽

Retinal Ganglion ◽

Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

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Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites ◽

10.3390/metabo11070422 ◽

2021 ◽

Vol 11 (7) ◽

pp. 422

Author(s):

Zhanat Koshenov ◽

Furkan E. Oflaz ◽

Martin Hirtl ◽

Johannes Pilic ◽

Olaf A. Bachkoenig ◽

...

Keyword(s):

Er Stress ◽

Energy Demand ◽

Molecular Mechanisms ◽

High Energy ◽

Human Neuroblastoma Cell ◽

Mitochondrial Bioenergetics ◽

Dependent Manner ◽

Human Neuroblastoma ◽

Sigma 1 Receptor ◽

Sigma 1

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

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Field Conversion of a Low-Firing Frame 7B Gas Turbine Power Plant to Ultra-Low Emission Combustion

Volume 3: Coal, Biomass and Alternative Fuels; Cycle Innovations; Electric Power; Industrial and Cogeneration ◽

10.1115/gt2015-42937 ◽

2015 ◽

Author(s):

Nicolas Demougeot ◽

Jeffrey A. Benoit

Keyword(s):

Power Plant ◽

Gas Turbine ◽

Energy Demand ◽

Water Injection ◽

Cost Benefit ◽

High Energy ◽

Nox Emissions ◽

Environmental Controls ◽

Low Emission ◽

Technical Discussion

The search for power plant sustainability options continues as regulating agencies exert more stringent industrial gas turbine emission requirements on operators. Purchasing power for resale, de-commissioning current capabilities altogether and repowering by replacing or converting existing equipment to comply with emissions standards are economic-driven options contemplated by many mature gas turbine operators. NRG’s Gilbert power plant based in Milford, NJ began commercial operation in 1974 and is fitted with four (4) natural gas fired GE’s 7B gas turbine generators with two each exhausting to HRSG’s feeding one (1) steam turbine generator. The gas turbine units, originally configured with diffusion flame combustion systems with water injection, were each emitting 35 ppm NOx with the New Jersey High Energy Demand Day (HEED) regulatory mandate to reduce NOx emissions to sub 10 ppm by May 1st, 2015. Studies were conducted by the operator to evaluate the economic viability & installation of environmental controls to reduce NOx emissions. It was determined that installation of post-combustion environmental controls at the facility was both cost prohibitive and technically challenging, and would require a fundamental reconfiguration of the facility. Based on this economic analysis, the ultra-low emission combustion system conversion package was selected as the best cost-benefit solution. This technical paper will focus on the ultra low emissions technology and key features employed to achieve these low emissions, a description of the design challenges and solution to those, a summary of the customer considerations in down selecting options and an overview of the conversion scope. Finally, a technical discussion of the low emissions operational flexibility will be provided including performance results of the converted units.

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