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

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.

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

2019 ◽  
Vol 218 (3) ◽  
pp. 909-928 ◽  
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 ◽  
Atp Depletion ◽  
Energy Demands ◽  
Transport Chain ◽  
Atm Gene ◽  
Cerebellar Purkinje Cells

Ataxia-telangiectasia (A-T) is an autosomal recessive disease caused by mutation of the ATM gene and is characterized by loss of cerebellar Purkinje cells, neurons with high physiological activity and dynamic ATP demands. Here, we show that depletion of ATP generates reactive oxygen species that activate ATM. We find that when ATM is activated by oxidative stress, but not by DNA damage, ATM phosphorylates NRF1. This leads to NRF1 dimerization, nuclear translocation, and the up-regulation of nuclear-encoded mitochondrial genes, thus enhancing the capacity of the electron transport chain (ETC) and restoring mitochondrial function. In cells lacking ATM, cells replenish ATP poorly following surges in energy demand, and chronic ATP insufficiency endangers cell survival. We propose that in the absence of ATM, cerebellar Purkinje cells cannot respond adequately to the increase in energy demands of neuronal activity. Our findings identify ATM as a guardian of mitochondrial output, as well as genomic integrity, and suggest that alternative fuel sources may ameliorate A-T disease symptoms.

scholarly journals Mitochondrial Dysfunction as a Novel Target for Neuroprotective Nutraceuticals in Ocular Diseases

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1950
Author(s):  
Chun-Ping Huang ◽  
Yi-Wen Lin ◽  
Yu-Chuen Huang ◽  
Fuu-Jen Tsai
Keyword(s):  
Free Radicals ◽  
Mitochondrial Dysfunction ◽  
Energy Demand ◽  
Early Stage ◽  
Mitochondrial Gene ◽  
High Energy ◽  
Neuroprotective Effects ◽  
Retinal Cells ◽  
Health Care Applications ◽  
Novel Target

The eyes require a rich oxygen and nutrient supply; hence, the high-energy demand of the visual system makes it sensitive to oxidative stress. Excessive free radicals result in mitochondrial dysfunction and lead to retinal neurodegeneration, as an early stage of retinal metabolic disorders. Retinal cells are vulnerable because of their coordinated interaction and intricate neural networks. Nutraceuticals are believed to target multiple pathways and have shown neuroprotective benefits by scavenging free radicals and promoting mitochondrial gene expression. Furthermore, encouraging results demonstrate that nutraceuticals improve the organization of retinal cells and visual functions. This review discusses the mitochondrial impairments of retinal cells and the mechanisms underlying the neuroprotective effects of nutraceuticals. However, some unsolved problems still exist between laboratory study and clinical therapy. Poor bioavailability and bioaccessibility strongly limit their development. A new delivery system and improved formulation may offer promise for health care applications.

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

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1402
Author(s):  
Bledi Petriti ◽  
Pete A. Williams ◽  
Gerassimos Lascaratos ◽  
Kai-Yin Chau ◽  
David F. Garway-Heath
Keyword(s):  
Mitochondrial Function ◽  
Energy Demand ◽  
Redox State ◽  
High Energy ◽  
Therapeutic Modality ◽  
Retinal Ganglion ◽  
Atp Production ◽  
Potential Biomarker ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Susceptibility And Resistance

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.

Abstract 1571: Hibernating Myocardium has Reduced High Energy Phosphate Levels and a Preconditioning-Like Effect with Slower ATP Depletion in Response to Acute Ischemia

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Qingsong Hu ◽  
Gen Suzuk ◽  
John M Canty ◽  
James A Fallavollita
Keyword(s):  
High Energy ◽  
Atp Depletion ◽  
Energy Utilization ◽  
Hibernating Myocardium ◽  
Wall Thickening ◽  
Acute Ischemia ◽  
High Energy Phosphates ◽  
High Energy Phosphate ◽  
Chronic Coronary Artery Disease ◽  
Atp Levels

Background. Pigs with a chronic LAD stenosis develop hibernating myocardium with contractile dysfunction and reduced resting flow. We hypothesized that this reduced energy utilization preserves ATP and protects the heart from irreversible injury during acute ischemia. Methods. Pigs with hibernating myocardium were studied 3-months after instrumentation with a 1.5 mm proximal LAD stenosis (n=7). Hibernating myocardium was confirmed by reduced LAD wall thickening (2.4±0.2 vs.6.1±0.6 mm in remote, p<0.05) and reduced resting flow (0.95±0.15 vs. 1.66±0.29 ml/min/g in remote, p<0.05) without infarction. Subendocardial samples were rapidly excised from propofol anesthetized pigs and serial depletion of high energy phosphates quantified by HPLC (in μmol/g dry weight) during simulated total ischemia in vitro (37°C). Results. At Baseline, ATP and ADP were significantly reduced in the hibernating LAD region in comparison to controls (n=8, Table ), with preserved CP/ATP and ATP/ADP ratios. During simulated ischemia, hibernating myocardium displayed a markedly reduced rate of ATP depletion (ΔATP), with ATP levels at 20 min significantly higher than control (Table ). Higher ATP levels were maintained throughout 80 min of ischemia. Interestingly, identical preservation of high energy phosphates occurred in the remote normally perfused region of hearts with hibernating myocardium (Table ). Conclusion. These data indicate that there is a balanced reduction in high energy phosphate levels in hibernating myocardium with chronic protection from ischemia manifested by a slower rate of ATP depletion during acute ischemia. This preconditioning-like effect is global suggesting that it arises from stimuli that are not directly related to ischemia. This raises the possibility that stretch from cyclical elevations in LV filling pressure or a circulating factor released from the heart in response to ischemia can protect the heart in chronic coronary artery disease.

scholarly journals Cardiac mitochondrial function depends on BUD23 mediated ribosome programming

eLife ◽  
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.

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

Reproduction ◽  
2000 ◽  
pp. 143-149 ◽  
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.

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

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.

scholarly journals IoT Platform for Energy Sustainability in University Campuses

Sensors ◽  
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.

scholarly journals The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 489
Author(s):  
Hilary Y. Liu ◽  
Jenna R. Gale ◽  
Ian J. Reynolds ◽  
John H. Weiss ◽  
Elias Aizenman
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Neuronal Damage ◽  
Mitochondrial Fission ◽  
Permeability Transition ◽  
High Energy ◽  
Atp Depletion ◽  
Ros Generation ◽  
Cellular Functions ◽  
Calcium Deregulation ◽  
Energy Demands

Zinc is a highly abundant cation in the brain, essential for cellular functions, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential (MMP), leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and excitotoxic calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

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

Metabolites ◽  
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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