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 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 Enhanced oxidative capacity of ground squirrel brain mitochondria during hibernation

2017 ◽  
Vol 312 (3) ◽  
pp. R301-R310 ◽  
Author(s):  
Mallory A. Ballinger ◽  
Christine Schwartz ◽  
Matthew T. Andrews
Keyword(s):  
Ground Squirrel ◽  
Energy Demand ◽  
Mitochondrial Gene ◽  
Nuclear Gene ◽  
Oxidative Capacity ◽  
Brain Mitochondria ◽  
Ground Squirrels ◽  
Mitochondrial Bioenergetics ◽  
Energy Demands ◽  
Transport Chain

During hibernation, thirteen-lined ground squirrels ( Ictidomys tridecemlineatus) regularly cycle between bouts of torpor and interbout arousal (IBA). Most of the brain is electrically quiescent during torpor but regains activity quickly upon arousal to IBA, resulting in extreme oscillations in energy demand during hibernation. We predicted increased functional capacity of brain mitochondria during hibernation compared with spring to accommodate the variable energy demands of hibernation. To address this hypothesis, we examined mitochondrial bioenergetics in the ground squirrel brain across three time points: spring (SP), torpor (TOR), and IBA. Respiration rates of isolated brain mitochondria through complex I of the electron transport chain were more than twofold higher in TOR and IBA than in SP ( P < 0.05). We also found a 10% increase in membrane potential between hibernation and spring ( P < 0.05), and that proton leak was lower in TOR and IBA than in SP. Finally, there was a 30% increase in calcium loading in SP brain mitochondria compared with TOR and IBA ( P < 0.01). To analyze brain mitochondrial abundance between spring and hibernation, we measured the ratio of copy number in a mitochondrial gene ( ND1) vs. a nuclear gene ( B2M) in frozen cerebral cortex samples. No significant differences were observed in DNA copies between SP and IBA. These data show that brain mitochondrial bioenergetics are not static across the year and suggest that brain mitochondria function more effectively during the hibernation season, allowing for rapid production of energy to meet demand when extreme physiological changes are occurring.

Ultrastorcture of Cerebellar Purkinje Cells in Rats Subjected To Partial Global Cerebral Ischemia

1985 ◽  
Vol 43 ◽  
pp. 674-675
Author(s):  
R.V.W. Dimlich ◽  
M.H. Biros
Keyword(s):  
Cerebral Ischemia ◽  
Purkinje Cells ◽  
Cell Types ◽  
Microscopic Level ◽  
Global Cerebral Ischemia ◽  
Light Microscopic Level ◽  
Cerebellar Damage ◽  
Cerebellar Injury ◽  
Cerebellar Purkinje Cells ◽  
Cell Changes

In severe cerebral ischemia, Purkinje cells of the cerebellum are one of the cell types most vulnerable to anoxic damage. In the partial (forebrain) global ischemic (PGI) model of the rat, Paljärvi noted at the light microscopic level that cerebellar damage is inconsistant and when present, milder than in the telencephalon, diencephalon and rostral brain stem. Cerebellar injury was observed in 3 of 4 PGI rats following 5 minutes of reperfusion but in none of the rats after 90 min of reperfusion. To evaluate a time between these two extremes (5 and 90 min), the present investigation used the PGI model to study the effects of ischemia on the ultrastructure of cerebellar Purkinje cells in rats that were sacrificed after 30 min of reperfusion. This time also was chosen because lactic acid that is thought to contribute to ischemic cell changes in PGI is at a maximum after 30 min of reperfusion.

scholarly journals Characterization of starvation-induced autophagy in cerebellar Purkinje cells of pHluorin-mKate2-human LC3B transgenic mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Alejandro Oliva Trejo ◽  
Isei Tanida ◽  
Chigure Suzuki ◽  
Soichiro Kakuta ◽  
Norihiro Tada ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Purkinje Cells ◽  
Cerebellar Purkinje Cells

scholarly journals Experimental Data and Simulations of Performance and Thermal Comfort in a Typical Mediterranean House

Energies ◽  
2021 ◽  
Vol 14 (11) ◽  
pp. 3311
Author(s):  
Víctor Pérez-Andreu ◽  
Carolina Aparicio-Fernández ◽  
José-Luis Vivancos ◽  
Javier Cárcel-Carrasco
Keyword(s):  
Energy Efficiency ◽  
Thermal Comfort ◽  
Energy Demand ◽  
Natural Ventilation ◽  
Thermal Characterization ◽  
Energy Performance ◽  
Building Stock ◽  
Energy Demands ◽  
Dwelling House ◽  
Account Standard

The number of buildings renovated following the introduction of European energy-efficiency policy represents a small number of buildings in Spain. So, the main Spanish building stock needs an urgent energy renovation. Using passive strategies is essential, and thermal characterization and predictive tests of the energy-efficiency improvements achieving acceptable levels of comfort for their users are urgently necessary. This study analyzes the energy performance and thermal comfort of the users in a typical Mediterranean dwelling house. A transient simulation has been used to acquire the scope of Spanish standards for its energy rehabilitation, taking into account standard comfort conditions. The work is based on thermal monitoring of the building and a numerical validated model developed in TRNSYS. Energy demands for different models have been calculated considering different passive constructive measures combined with real wind site conditions and the behavior of users related to natural ventilation. This methodology has given us the necessary information to decide the best solution in relation to energy demand and facility of implementation. The thermal comfort for different models is not directly related to energy demand and has allowed checking when and where the measures need to be done.

Sign in / Sign up

Export Citation Format

Share Document