Modeling Mitochondrial Function and Its Role in Disease

Jafri, M. Saleet; Kumar, Rashmi

doi:10.1016/b978-0-12-397897-4.00001-2

Cited by 9 publications

(8 citation statements)

References 30 publications

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“…This is particularly important because the dual physiological and detrimental roles of Ca 2+ in the mitochondrial matrix. 11 Ipsilateral cortex homogenates (50 lL) obtained from 10-day-old treated mice were added to standard swelling incubation medium (100 mM KCl, 50 mM sucrose, 10 mM HEPES and 5 mM KH 2 PO 4 ) and the basal mitochondrial absorbance was monitored during 3 min in microplates. Mitochondrial substrates PMGSA (3.5 mM pyruvate, 4.5 mM malate, 4.5 mM glutamate, 1.2 mM succinate and 100 lM of adenosine diphosphate [ADP]) were added to energize mitochondria and support ATP synthesis.…”

Section: Mitochondrial Calcium Handlingmentioning

confidence: 99%

“…In contrast, the mitochondrial sodium-calcium-lithium exchanger (NCLX), balances Ca 2+ influx by extruding one Ca 2+ ion in exchange for three sodium ions (Na + ). 11 Further, the NCLX is proposed to be responsible for mitochondrial Ca 2+ extrusion in excitable cells like neurons. Thus, it has been proposed that TBI primes neurons to die due to the confluence of mitochondrial dysfunction and subsequent degenerative processes.…”

Section: Introductionmentioning

confidence: 99%

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Testosterone Administration after Traumatic Brain Injury Reduces Mitochondrial Dysfunction and Neurodegeneration

Carteri

Kopczynski

Rodolphi

et al. 2019

Journal of Neurotrauma

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Traumatic brain injury (TBI) increases Ca 2+ influx into neurons and desynchronizes mitochondrial function leading to energy depletion and apoptosis. This process may be influenced by brain testosterone (TS) levels, which are known to decrease after TBI. We hypothesized that a TS-based therapy could preserve mitochondrial neuroenergetics after TBI, thereby reducing neurodegeneration. C57BL/6J mice were submitted to sham treatment or severe parasagittal controlled cortical impact (CCI) and were subcutaneously injected with either vehicle (VEH-SHAM and VEH-CCI) or testosterone cypionate (15 mg/kg, TS-CCI) for 10 days. Cortical tissue homogenates ipsilateral to injury were used for neurochemical analysis. The VEH-CCI group displayed an increased Ca 2+-induced mitochondrial swelling after the addition of metabolic substrates (pyruvate, malate, glutamate, succinate, and adenosine diphosphate [PMGSA]). The addition of Na + stimulated mitochondrial Ca 2+ extrusion through Na + /Ca 2+ /Li + exchanger (NCLX) in VEH-SHAM and TS-CCI, but not in the VEH-CCI group. Reduction in Ca 2+ efflux post-injury was associated with impaired mitochondrial membrane potential formation/dissipation, and decreased mitochondrial adenosine triphosphate (ATP)-synthase coupling efficiency. Corroborating evidence of mitochondrial uncoupling was observed with an increase in H 2 O 2 production post-injury, but not in superoxide dismutase (SOD2) protein levels. TS administration significantly reduced these neuroenergetic alterations. At molecular level, TS prevented the increase in pTau Ser396 and alpha-Spectrin fragmentation by the Ca 2+ dependent calpain-2 activation, and decreased both caspase-3 activation and Bax/BCL-2 ratio, which suggests a downregulation of mitochondrial apoptotic signals. Search Tool for the Retrieval of Interacting Genes/Proteins database provided two distinct gene/protein clusters, ''upregulated and downregulated,'' interconnected through SOD2. Therefore, TS administration after a severe CCI improves the mitochondrial Ca 2+ extrusion through NCLX exchanger and ATP synthesis efficiency, ultimately downregulating the overexpression of molecular drivers of neurodegeneration.

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Section: Mitochondrial Calcium Handlingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Testosterone Administration after Traumatic Brain Injury Reduces Mitochondrial Dysfunction and Neurodegeneration

Carteri

Kopczynski

Rodolphi

et al. 2019

Journal of Neurotrauma

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“…These parameters are indeed included in the model plausible solutions for aged and for stressed worms (Figure 4C to 4F). Excessive ROS production is related to increased open probability of the intracellular channels on Ca 2+ stores, as is the case with RyR receptors (105,106). Additionally, oxidative stress leading to promoted Ca 2+ efflux from the stores into the cytoplasm (107, 108) has been reported also through IP 3 receptors, because of -SH groups oxidation (39) and due to increased production of IP 3 (107).…”

Section: Ca 2+ Dynamics Reveal the Effect Of Age And Stress On Ca 2+ mentioning

confidence: 99%

A mathematical and computational model of the calcium dynamics inCaenorhabditis elegansASH sensory neuro

Mirzakhalili

Epureanu

Gourgou

2017

Preprint

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We propose a mathematical and computational model that captures the stimulusgenerated Ca 2+ transients in the C. elegans ASH sensory neuron. The model is built based on biophysical events and molecular cascades known to unfold as part of neurons' Ca 2+ homeostasis mechanism, as well as on Ca 2+ signaling events. The state of ion channels is described by their probability of being activated or inactivated, and the remaining molecular states are based on biochemically defined kinetic equations with phenomenological adjustments. We estimate the parameters of the model using experimental data of hyperosmotic stimulus-evoked Ca 2+ transients detected with a FRET sensor in young and aged worms, unstressed and exposed to oxidative stress. We use a hybrid optimization method composed of a multi-objective genetic algorithm and nonlinear least-squares to estimate the model parameters. We first obtain the model parameters for young unstressed worms. Next, we use these values of the parameters as a starting point to identify the model parameters for stressed and aged worms. We show that the model, in combination with experimental data, corroborates literature results. In addition, we demonstrate that our model can be used to predict ASH response to complex combinations of stimulation pulses. The proposed model includes for the first time the ASH Ca 2+ dynamics observed during both "on" and "off"responses. This mathematical and computational effort is the first to propose a dynamic model of the Ca 2+ transients' mechanism in C. elegans neurons, based on biochemical pathways of the cell's Ca 2+ homeostasis machinery.Key words: C. elegans, calcium dynamics, ASH neuron, aging, oxidative stress Significance StatementC. elegans is widely used as a model system for monitoring neuronal Ca 2+ transients.The ASH neuron is the subject of several such studies, primarily due to its key importance as a polymodal nociceptor. However, despite its pivotal role in C. elegans biology, and the special characteristics of its stimulus-evoked Ca2 + transients (e.g., the peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/201962 doi: bioRxiv preprint first posted online Oct. 12, 2017; "off" response), no mathematical or computational model has been developed to include special features of ASH Ca 2+ dynamics, i.e. the "off" response. The model includes for the first time the ASH Ca 2+ dynamics observed during both "on" and "off" responses, and is the first to propose a dynamical model of the C. elegans Ca 2+ transients' mechanism based on biochemical pathways of the cell's Ca 2+ homeostasis machinery.

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“…Another model incorporated antioxidant systems to account for the fact that most ROS experimental data used to inform models is collected employing techniques that detect H 2 O 2 diffusing from mitochondria as a surrogate measurement for superoxide production ( Gauthier et al, 2013 ). Fewer models have linked ROS production in mitochondria to other cellular processes ( Jafri and Kumar, 2014 ). The role of ROS in apoptosis has been included in models regulating mitochondrial membrane permeabilization ( Jacob et al, 2016 ) and in transition pore opening ( Bagci et al, 2006 ).…”

Section: Current Efforts In Biomarker Modelingmentioning

confidence: 99%

Evaluating biomarkers to model cancer risk post cosmic ray exposure

Sridharan

Asaithamby

Blattnig

et al. 2016

Life Sciences in Space Research

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Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Chronic exposure to cosmic rays in the context of the complex deep space environment may place astronauts at high cancer risk. To estimate this risk, it is critical to understand how radiation-induced cellular stress impacts cell fate decisions and how this in turn alters the risk of carcinogenesis. Exposure to the heavy ion component of cosmic rays triggers a multitude of cellular changes, depending on the rate of exposure, the type of damage incurred and individual susceptibility. Heterogeneity in dose, dose rate, radiation quality, energy and particle flux contribute to the complexity of risk assessment. To unravel the impact of each of these factors, it is critical to identify sensitive biomarkers that can serve as inputs for robust modeling of individual risk of cancer or other long-term health consequences of exposure. Limitations in sensitivity of biomarkers to dose and dose rate, and the complexity of longitudinal monitoring, are some of the factors that increase uncertainties in the output from risk prediction models. Here, we critically evaluate candidate early and late biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions. Some of the biomarkers we have reviewed include complex clustered DNA damage, persistent DNA repair foci, reactive oxygen species, chromosome aberrations and inflammation. Other biomarkers discussed, often assayed for at longer points post exposure, include mutations, chromosome aberrations, reactive oxygen species and telomere length changes. We discuss the relationship of biomarkers to different potential cell fates, including proliferation, apoptosis, senescence, and loss of stemness, which can propagate genomic instability and alter tissue composition and the underlying mRNA signatures that contribute to cell fate decisions. Our goal is to highlight factors that are important in choosing biomarkers and to evaluate the potential for biomarkers to inform models of post exposure cancer risk. Because cellular stress response pathways to space radiation and environmental carcinogens share common nodes, biomarker-driven risk models may be broadly applicable for estimating risks for other carcinogens.

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Modeling Mitochondrial Function and Its Role in Disease

Cited by 9 publications

References 30 publications

Testosterone Administration after Traumatic Brain Injury Reduces Mitochondrial Dysfunction and Neurodegeneration

Testosterone Administration after Traumatic Brain Injury Reduces Mitochondrial Dysfunction and Neurodegeneration

A mathematical and computational model of the calcium dynamics inCaenorhabditis elegansASH sensory neuro

Evaluating biomarkers to model cancer risk post cosmic ray exposure

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