Fission Process Research Articles

Mutated FANCA Gene Role in the Modulation of Energy Metabolism and Mitochondrial Dynamics in Head and Neck Squamous Cell Carcinoma.

Fanconi Anaemia (FA) is a rare recessive genetic disorder characterized by a defective DNA repair mechanism. Although aplastic anaemia is the principal clinical sign in FA, patients develop a head and neck squamous cell carcinoma (HNSCC) with a frequency 500–700 folds higher than the general population, which appears more aggressive, with survival of under two years. Since FA gene mutations are also associated with a defect in the aerobic metabolism and an increased oxidative stress accumulation, this work aims to evaluate the effect of FANCA mutation on the energy metabolism and the relative mitochondrial quality control pathways in an HNSCC cellular model. Energy metabolism and cellular antioxidant capacities were evaluated by oximetric, luminometric, and spectrophotometric assays. The dynamics of the mitochondrial network, the quality of mitophagy and autophagy, and DNA double-strand damage were analysed by Western blot analysis. Data show that the HNSCC cellular model carrying the FANCA gene mutation displays an altered electron transport between respiratory Complexes I and III that does not depend on the OxPhos protein expression. Moreover, FANCA HNSCC cells show an imbalance between fusion and fission processes and alterations in autophagy and mitophagy pathways. Together, all these alterations associated with the FANCA gene mutation cause cellular energy depletion and a metabolic switch to glycolysis, exacerbating the Warburg effect in HNSCC cells and increasing the growth rate. In addition, the altered DNA repair due to the FANCA mutation causes a higher accumulation of DNA damage in the HNSCC cellular model. In conclusion, changes in energy metabolism and mitochondrial dynamics could explain the strict correlation between HNSCC and FA genes, helping to identify new therapeutic targets.

Triplet-pair spin signatures from macroscopically aligned heteroacenes in an oriented single crystal

The photo-driven process of singlet fission generates coupled triplet pairs (TT) with fundamentally intriguing and potentially useful properties. The quintet 5TT0 sublevel is particularly interesting for quantum information because it is highly entangled, is addressable with microwave pulses, and could be detected using optical techniques. Previous theoretical work on a model Hamiltonian and nonadiabatic transition theory, called the JDE model, has determined that this sublevel can be selectively populated if certain conditions are met. Among the most challenging, the molecules within the dimer undergoing singlet fission must have their principal magnetic axes parallel to one another and to an applied Zeeman field. Here, we present time-resolved electron paramagnetic resonance (TR-EPR) spectroscopy of a single crystal sample of a tetracenethiophene compound featuring arrays of dimers aligned in this manner, which were mounted so that the orientation of the field relative to the molecular axes could be controlled. The observed spin sublevel populations in the paired TT and unpaired (T+T) triplets are consistent with predictions from the JDE model, including preferential 5TT0 formation at z ‖ B0, with one caveat-two 5TT spin sublevels have little to no population. This may be due to crossings between the 5TT and 3TT manifolds in the field range investigated by TR-EPR, consistent with the intertriplet exchange energy determined by monitoring photoluminescence at varying magnetic fields.

Removal of Radioactive Gas by Zeolite Filter From Nuclear Power Plants

During the normal operation of nuclear power plants, some radioactive wastes are produced in the form of particles or aerosol gas in the reactor building. Particulate radioactive aerosols can be produced in a wide variety of particle sizes, possibly in combination with non-radioactive aerosols. Emission of corrosion products and fission products that are activated by the effect of nuclear rays generate aerosols from two sources. These; are created by the adsorption of gases generated by radioactive decay and volatile radionuclides formed during the fission process on the present suspended material. The most important volatile radionuclides that form the gaseous radioactive waste produced during the normal operation of nuclear power plants are halogens, noble gases, tritium, and carbon-14. The composition and amount of radioactivity present in the various airborne waste streams depend largely on the reactor type and release path. All gaseous waste from nuclear power plants must be treated before discharging into the atmosphere. In this paper, radioactive radon gas was used to represent the radioactive gases generated from nuclear power plants and natural zeolite was used as adsorbent material for radon removal. A series of experiments were conducted to measure the performance of the filter made in the zeolite. First of all, an approximate particle distribution size in the range of 1 to 3 mm was obtained by grinding natural zeolite. The ground material was then compressed in cylindrical adsorbent moulds of 35 mm diameter and 10 mm height. After the moulds were filled with the material, they were dried by heating to 110 ° C for 24 hours. At the end of the heat treatment, the adsorbent beds were cooled and connected to the test apparatus. RAD7 radon test device was used in the experiments. The RAD7 is a portable instrument that uses a solid-state alpha detector to measure radon gas concentrations in the range of 4.0-750,000 Bq / m3. The sampler of the RAD7 device works by drawing an air sample from an inlet filter into a 0.7 L sample cell covered with an electrical conductor. At the centre of the hemisphere, the cell is a planar silicon detector implanted with an ion to measure radioactivity. As result of the experiments, it shows that the zeolite filter absorbs 85% radioactive radon gas and can be used as an air filter in nuclear power plants.

A general framework for describing photofission observables of actinides at an average excitation energy below 30 MeV * *Supported by the National Natural Science Foundation of China (11675075), Independent research project of key laboratory of plasma physics, CAEP (JCKYS2021212009) and Hengyang Municipal Science and Technology Project (202150054076)

A reasonable prediction of photofission observables plays a paramount role in understanding the photofission process and guiding various photofission-induced applications, such as short-lived isotope production, nuclear waste disposal, and nuclear safeguards. However, the available experimental data for photofission observables are limited, and the existing models and programs have mainly been developed for neutron-induced fission processes. In this study, a general framework is proposed for characterizing the photofission observables of actinides, including the mass yield distributions (MYD) and isobaric charge distributions (ICD) of fission fragments and the multiplicity and energy distributions of prompt neutrons (np ) and prompt γ rays (γ p ). The framework encompasses various systematic neutron models and empirical models considering the Bohr hypothesis and does not rely on the experimental data as input. These models are then validated individually against experimental data at an average excitation energy below 30 MeV, which shows the reliability and robustness of the general framework. Finally, we employ this framework to predict the characteristics of photofission fragments and the emissions of prompt particles for typical actinides including 232Th, 235, 238U and 240Pu. It is found that the 238U(γ, f) reaction is more suitable for producing neutron-rich nuclei compared to the 232Th(γ, f) reaction. In addition, the average multiplicity number of both np and γ p increases with the average excitation energy.

Mitochondrial Dysfunction in Oxidative Stress-Mediated Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is the most common contributor to low back pain (LBP). Recent studies have found that oxidative stress and reactive oxygen species (ROS) play an important role in IVDD. As a by‐product of aerobic respiration, ROS is mainly produced in the mitochondria by the electron transport chain and other mitochondrial located proteins. With the excessive accumulation of ROS, mitochondria are also the primary target of ROS attack in disc cells. A disrupted balance between intracellular ROS production and antioxidant capacity will lead to oxidative stress, which is the key contributor to cell apoptosis, cell senescence, excessive autophagy, and mitochondrial dysfunction. As the pivotal ingredient of oxidative stress, mitochondrial dysfunction manifests as imbalanced mitochondrial dynamics and dysregulated mitophagy. Mitochondria can alter their own dynamics through the process of fusion and fission, so that disabled mitochondria can be separated from the mitochondrial pool. Moreover, mitophagy participates by clearing these dysfunctional mitochondria. Abnormality in any of these processes either increases the production or decreases the clearance of ROS, leading to a vicious cycle that results in the death of intervertebral disc cells in large quantities, combined with degradation of the extracellular matrix and overproduction of matrix metalloproteinase. In this review, we explain the changes in mitochondrial morphology and function during oxidative stress‐mediated IVDD and highlight the important role of mitochondria in this process. Eventually, we summarize the IVDD therapeutic strategies targeting mitochondrial dysfunction based on current understanding of the role of oxidative stress in IVDD.

Observation of Reverse Intersystem‐Crossing From the Upper‐Level Triplet to Lowest Singlet Excitons (T2→S1) in Tetra(t‐butyl)rubrene‐Based OLEDs for Enhanced Light‐Emission

AbstractHigh external quantum efficiency (EQE) up to 25% has recently been reported from tetra(t‐butyl)rubrene (TBRb)‐based organic light‐emitting diodes (OLEDs), but its physical origin is still vague. Herein, using the featured responses of the evolution processes of electron‐hole pairs to an external magnetic field, an unreported high‐level reverse intersystem‐crossing (HL‐RISC) from upper‐level triplet to lowest singlet excitons (T2→S1) is observed when T2 is well confined in the active layer of pure TBRb. This HL‐RISC channel becomes stronger with lowering operational temperatures because it is not an endothermic process. Due to the larger separation distance of TBRb molecules with four tert‐butyl groups, the intersystem‐crossing (ISC) process of polaron pairs is stronger than the singlet fission (SF) process existing in pure TBRb, which is markedly different from the behaviors of excited states in pure rubrene (Rb) with negligible ISC and strong SF. More importantly, HL‐RISC is stronger in TBRb than in Rb‐doped systems, which is consistent with the higher EQE frequently reported from TBRb‐doped OLEDs. Thus, this work deepens the physical understanding of microscopic processes in typical organic multi‐functional semiconductors of TBRb or Rb and paves the way for fabricating further high‐efficiency yellow OLEDs.

Nuclear receptor Nur77 protects against oxidative stress by maintaining mitochondrial homeostasis via regulating mitochondrial fission and mitophagy in smooth muscle cell

Angiotensin II (AngII) induces disruption of mitochondrial homeostasis and oxidative stress. Nuclear receptor NR4A1 (Nur77) plays an important role in vascular smooth muscle cells (VSMCs) function. However, the role of Nur77 in AngII-induced mitochondrial dynamics and oxidative stress in VSMCs remains unknown. In an in vitro model of AngII-treated cells, we discovered that Nur77 knockout aggravated AngII-induced oxidative stress in VSMCs, whereas activation of Nur77 by celastrol diminished them. Concomitantly, disturbance of mitochondrial dynamics induced by AngII was further exacerbated in Nur77 deficient VSMCs compared to wild-type (WT) VSMCs. Interestingly, Nur77 deletion increased mitochondrial fission but not fusion as evidenced by upregulated fission related genes (Fis1 and Drp1) but not fusion (Opa1 and Mfn2) under AngII stimulation in VSMCs. Mechanically, Nur77 could directly bind to the promoter regions of Fis1 and Drp1 and repress their transcription. Furthermore, we observed that Nur77 additionally promoted mitochondrial homeostasis by increasing mitophagic flux in a transcription-independent manner upon AngII challenge. By using an in vivo model of AngII-induced abdominal aortic aneurysm (AAA), we finally validated the protective role of Nur77 involved in the mitochondrial fission process and mitophagic flux in aortas, which was correlated with the occurrence and development of AAA in AngII-infused mice. Our data defines an essential role of Nur77 in regulating oxidative stress by maintaining mitochondrial homeostasis in VSMCs via both transcription-dependent and transcription-independent manner, supporting the therapeutic potential of Nur77 targeting in vascular diseases.

Uric Acid Enhances Neurogenesis in a Parkinsonian Model by Remodeling Mitochondria.

BackgroundAdult neurogenesis is the process of generating new neurons to enter neural circuits and differentiate into functional neurons. However, it is significantly reduced in Parkinson’s disease (PD). Uric acid (UA), a natural antioxidant, has neuroprotective properties in patients with PD. This study aimed to investigate whether UA would enhance neurogenesis in PD.MethodsWe evaluated whether elevating serum UA levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model would restore neurogenesis in the subventricular zone (SVZ). For a cellular model, we primary cultured neural precursor cells (NPCs) from post-natal day 1 rat and evaluated whether UA treatment promoted cell proliferation against 1-methyl-4-phenylpyridinium (MPP+).ResultsUric acid enhanced neurogenesis in both in vivo and in vitro parkinsonian model. UA-elevating therapy significantly increased the number of bromodeoxyuridine (BrdU)-positive cells in the SVZ of PD animals as compared to PD mice with normal UA levels. In a cellular model, UA treatment increased the expression of Ki-67. In the process of modulating neurogenesis, UA elevation up-regulated the expression of mitochondrial fusion markers.ConclusionIn MPTP-induced parkinsonian model, UA probably enhanced neurogenesis via regulating mitochondrial dynamics, promoting fusion machinery, and inhibiting fission process.

Impact of exercise training on mitochondrial dynamics during ischemia-reperfusion

Mitochondrial fission is a key trigger of cardiac ischemia-reperfusion injuries (IR) injuries. Despite exercise training (ExTr) is known as an efficient strategy to protect the heart, its impact on the dynamic of the mitochondrial network remain to be investigated. To evaluate the impact of ExTr on the process of mitochondrial fission during IR. Isolated hearts from ExTr or Sedentary (Sed) rats were subjected to IR. Hearts samples were collected after 10 min of reperfusion for biochemical assays or electron microscopic analysis. Finally, DHR123 was used to detect ROS production on isolated cardiomyocytes treated or not with the mitochondrial fission inhibitor Mdivi1. We confirmed on isolated rat hearts that ExTr reduced heart sensitivity to IR. This was associated with lower ROS production evaluated by DHE fluorescence and higher mitochondria Ca2+ retention capacities. We next confirmed that IR was associated with mitochondrial fission as well as the translocation and activation of the Dynamin related protein 1 (Drp1), known as the central regulator of mitochondrial fission. Interestingly, ExTr limited both the activation of Drp1 and the fission of mitochondria. We also reported that ExTr tended to increase the level of Mfn2, known as a central regulator of mitochondrial fusion. Finally, on isolated cardiomyocytes stimulated with H2O2 to mimic IR, we reported that Mdivi1 impact the level of ROS production only in Sed cells. This confirms that mitochondrial fission was more pronounced in Sed cells and contributes to increased ROS production during IR. Altogether, our results support the hypothesis that ExTr is able to modulate the dynamic of the mitochondrial network during IR, which could participate to exercise-induced cardioprotection.

The Iodine Rush: Over- or Under-Iodination Risk in the Prophylactic Use of Iodine for Thyroid Blocking in the Event of a Nuclear Disaster.

Iodine is an essential element for the production of thyroid hormones (THs). Both deficient and excess iodine intakes may precipitate in adverse thyroidal events. Radioactive iodine (RI) is a common byproduct of nuclear fission processes. During nuclear emergencies RI may be released in a plume, or cloud, contaminating the environment. If inhaled or ingested, it may lead to internal radiation exposure and the uptake of RI mainly by the thyroid gland that absorbs stable iodine (SI) and RI in the same way. A dose of radiation delivered to the thyroid gland is a main risk factor for the thyroid cancer development. The SI prophylaxis helps prevent childhood thyroid cancer. The thyroid gland saturation with prophylactic SI ingestion, reduces the internal exposure of the thyroid by blocking the uptake of RI and inhibiting iodide organification. However, negative impact of inadequate SI intake must be considered. We provide an overview on the recommended iodine intake and the impact of SI and RI on thyroid in children and adolescents, discussing the benefits and adverse effects of the prophylactic SI for thyroid blocking during a nuclear accident. The use of SI for protection against RI may be recommended in cases of radiological or nuclear emergencies, moreover the administration of iodine for prophylactic purposes should be cautious. Benefits and risks should also be considered according to age. Adverse effects from iodine administration cannot be excluded. Precise indications are mandatory to use the iodine for thyroid blocking. Due to this natural adaption mechanism it’s possible to tolerate large doses of iodine without clinical effects, however, a prolonged assumption of the iodine when not needed can be dangerous and may precipitate in severe thyroidal and non-thyroidal negative effects.

Controlled synthesis of charged lignin nanocarriers by electrospray

An experimental investigation of synthesis of lignin nanoparticles using an electrospray system was systematically performed. This investigation demonstrated the control of size and charge distribution of lignin nanoparticles in the single-step electrospray process by tuning the operation parameters and precursor properties. The most important parameters include the liquid flow rate, the initial precursor concentration, and the electrical conductivity. A generalized theoretical model to predict the size and charge developed in our previous work is then verified for a variety of experimental conditions. Finally, we explored the formation mechanism of lignin nanoparticles with three different morphologies: solid sphere, hollow sphere, and elliptical solid. The lignin nanoparticle morphology depends on the competition between the solvent evaporation, the polymer diffusion inside the droplet, and the Coulombic fission processes. This work provides significant insights for fabricating charged nanocarriers for drug delivery applications.

Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics

Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase 9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.

Singlet fission photovoltaics: Progress and promising pathways

Singlet fission is a form of multiple exciton generation, which occurs in organic chromophores when a high-energy singlet exciton separates into two lower energy triplet excitons, each with approximately half the singlet energy. Since this process is spin-allowed, it can proceed on an ultrafast timescale of less than several picoseconds, outcompeting most other loss mechanisms and reaching quantitative yields approaching 200%. Due to this high quantum efficiency, the singlet fission process shows promise as a means of reducing thermalization losses in photovoltaic cells. This would potentially allow for efficiency improvements beyond the thermodynamic limit in a single junction cell. Efforts to incorporate this process into solar photovoltaic cells have spanned a wide range of device structures over the past decade. In this review, we compare and categorize these attempts in order to assess the state of the field and identify the most promising avenues of future research and development.

Identification of elongation factor‐2 as a novel regulator of mitochondrial fission

AbstractMitochondria continuously undergo morphologically dynamic processes of fusion and fission to maintain their size, shape, amount, and function; yet the precise molecular mechanisms by which mitochondrial dynamics is regulated remain to be fully elucidated. Here, we report a previous unappreciated but critical role of eukaryotic elongation factor 2 (eEF2) in regulating mitochondrial fission. eEF2, a G‐protein superfamily member encoded by EEF2 gene in humans, has long been appreciated as a promoter of the GTP‐dependent translocation of the ribosome during protein synthesis. We found unexpectedly in several types of cells that eEF2 was not only present in the cytosol but also in the mitochondria. Furthermore, we showed that mitochondrial length was significantly increased when the cells were subjected to silencing of eEF2 expression, suggesting a promotive role for eEF2 in the mitochondrial fission. Inversely, overexpression of eEF2 decreased mitochondrial length, suggesting an increase of mitochondrial fission. Inhibition of mitochondrial fission caused by eEF2 depletion was accompanied by alterations of cellular metabolism, as evidenced by a reduction of oxygen consumption and an increase of oxidative stress in the mitochondria. We further demonstrated that eEF2 and Drp1, a key driver of mitochondrial fission, colocalized at the mitochondria, as evidenced by microscopic observation, coimmunoprecipitation, and GST pulldown assay. Deletion of the GTP‐binding motif of eEF2 decreased its association with Drp1 and abrogated its effect on mitochondria fission. Moreover, we showed that wild‐type eEF2 stimulated GTPase activity of Drp1, whereas deletion of the GTP‐binding site of eEF2 diminished its stimulatory effect on GTPase activity. This work not only reveals a previously unrecognized function of eEF2 (i.e., promoting mitochondrial fission), but also uncovers the interaction of eEF2 with Drp1 as a novel regulatory mechanism of the mitochondrial dynamics. Therefore, eEF2 warrants further exploration for its potential as a therapeutic target for the mitochondria‐related diseases.Key Points We demonstrate that eEF‐2 localizes in the mitochondria, in addition to its presence in the cytosol. This study identifies eEF‐2 as a novel regulator of mitochondrial fission. This work uncovers the interaction of eEF‐2 with Drp1 and its effect on GTPase activity as a new mechanism that regulates mitochondrial dynamics.

Nudged elastic band approach to nuclear fission pathways

Background: The nuclear fission process is a dramatic example of the large-amplitude collective motion in which the nucleus undergoes a series of shape changes before splitting into distinct fragments. This motion can be represented by a pathway in the many-dimensional space of collective coordinates. Within a stationary framework rooted in a static collective Schr\"odinger equation, the collective action along the fission pathway determines the spontaneous fission half-lives as well as mass and charge distributions of fission fragments.Purpose: We study the performance and precision of various methods to determine the minimum-action and minimum-energy fission trajectories in the collective space.Methods: We apply the nudged elastic band method (NEB), grid-based methods, and the Euler-Lagrange approach to the collective action minimization in two- and three-dimensional collective spaces.Results: The performance of various approaches to the fission pathway problem is assessed by studying the collective motion along both analytic energy surfaces and realistic potential-energy surfaces obtained with the Skyrme-Hartree-Fock-Bogoliubov theory. The uniqueness and stability of the solutions is studied. The NEB method is capable of efficient determination of the exit points on the outer turning surface that characterize the most probable fission pathway and constitute the key input for fission studies. This method can also be used to accurately compute the critical points (i.e., local minima and saddle points) on the potential-energy surface of the fissioning nucleus that determine the static fission path. The dynamic programming method also performs quite well and it can be used in many-dimensional cases to provide initial conditions for the NEB calculations.Conclusions: The NEB method is the tool of choice for finding the least-action and minimum-energy fission trajectories. It will be particularly useful in large-scale static fission calculations of superheavy nuclei and neutron-rich fissioning nuclei contributing to the astrophysical $r$-process recycling.

Engineering Cavity Singlet Fission in Rubrene.

By employing the numerically exact multiple Davydov D2 ansatz, we study cavity-manipulated singlet fission that is mediated by polaritonic conical intersections for both one- and two-molecule systems. The population evolution of the TT state and the cavity photons is carefully examined in search for a high fission efficiency via cavity engineering. Several interesting mechanisms have been uncovered, such as photon-assisted singlet fission, system localization via a displaced photon state, and collective enhancement of the fission efficiency for the two-molecule system. It is also found that the system localization process in the two-molecule system differs substantially from that in the one-molecule system because of the appearance of a novel central polaritonic conical intersection in the two-molecule system. It has been demonstrated that the cavity-controlled singlet fission process can be switched on and off by controlling the average pumping photon number.

Acute Manipulation of Outer Membrane Phospholipid Composition Directly Alters Mitochondrial Dynamics and Ultrastructure

Mitochondria undergo coordinated rounds of fusion and fission that are critical for maintaining the functional integrity of this essential organelle. While a growing number of proteins have been identified as important regulators of mitochondrial dynamics, the direct role of membrane lipid composition during the fusion and fission processes is poorly understood. To address these shortcomings, we devised a protein‐engineering platform that allows for the acute remodeling of structural phospholipids within the outer mitochondrial membrane (OMM) of intact cells. Specifically, we modified a bacterial phospholipase C (Bacillus cereus (Bc)PI‐PLC) to initiate the rapid hydrolysis of phosphatidylinositol (PI) and locally generate diacylglycerol (DAG); an important intracellular signaling molecule and metabolic precursor that is used in diverse lipid biosynthetic pathways. Spatial restriction of enzyme activity was achieved using a chemically inducible system consisting of a rapamycin‐dependent dimerization module (FKBP‐BcPI‐PLC) along with an OMM targeting sequence tagged with the FKBP‐rapamycin binding domain (OMM‐FRB). Using these unique molecular tools, we show that recruitment of FKBP‐BcPI‐PLC to the OMM not only causes the expected local accumulation of DAG, but also initiates the rapid and uniform fragmentation of the mitochondrial network. Mitochondrial fission induced by FKBP‐BcPI‐PLC is accompanied by profound swelling of the mitochondrial matrix along with vesiculation of the inner mitochondrial membrane (IMM) and a general loss of cristae, which all occur within minutes of tethering FKBP‐BcPI‐PLC to the OMM. Expression of dominant‐negative constructs targeting essential GTPases known to regulate OMM fission suggest that both dynamin‐related protein 1 (Drp1) and dynamin 2 (Dnm2) work together to drive efficient BcPI‐PLC‐induced mitochondrial division. However, results using a validated Drp1 knockout cell line show that the loss of Drp1 alone is sufficient to prevent the mitochondrial fragmentation initiated by FKBP‐BcPI‐PLC recruitment, indicating that Drp1 likely functions upstream or independent of Dnm2 in this context. Interestingly, unlike the induced OMM fission, removal of Drp1 from cells does not prevent the matrix swelling or OMM constrictions observed in response to acute generation of DAG within the OMM. Ongoing experiments are now focused on characterizing new methods to sequentially metabolize the DAG generated within the OMM as well as investigate how local lipid composition influences the binding and oligomerization of membrane‐shaping proteins that may function in concert with Drp1 to regulate mitochondrial remodeling. Overall, these studies establish a direct relationship between lipid metabolism within the OMM and clinically relevant morphological changes that are known to manifest in mitochondrial‐associated diseases.

Diurnal Differences in Mitochondrial Bioenergetics is Lost in Bmal1 Knockout Rats

In the kidney, 95% of O2 consumed through mitochondrial respiration is used for Na+ transport. The circadian clock regulates Na+ transport with a necessary diurnal variation for optimal health. The circadian clock transcription factor BMAL1 is proposed to regulate mitochondrial bioenergetic function; however, this has not been extensively investigated in the kidney. Therefore, we tested the hypothesis that renal mitochondrial respiration may be impaired or altered in a novel Bmal1 clock gene knock‐out rat model and is associated with loss of diurnal control of Na+ excretion. Male and female global Bmal1+/+ and Bmal1‐/‐ rats at 12‐14 weeks of age maintained in a regular 12‐hour light/dark cycle was used to measure renal mitochondrial O2consumption. Outer renal medullary tissue was dissected and prepared for respiration measurements at either day (ZT2‐4) or night (ZT14‐16) periods to correspond with minimum and maximum whole‐body energy consumption as well as peak and trough BMAL1 protein expression, respectively (n = 10, Bmal1+/+; n = 22, Bmal1‐/‐). Respiration was assessed using permeabilized tissue in the Oroboros Oxygraph and analyzed using Data Lab 2 software (O2K, Oroboros Instruments GmbH). Mitochondrial gene expression analysis was assessed using digital drop PCR. Data from both sexes were combined for each genotype at the two time points and analyzed by two‐way ANOVA. Mitochondrial state 3 O2 consumption was significantly higher (main effect of genotype p = 0.0310) in Bmal1‐/‐ (118 ± 156 pmol/s*mg) compared to BMAL1+/+ rats (75 ± 15 pmol/s*mg; Tukey post‐hoc p = 0.0303). We also observed a significant increase in complex IV activity in Bmal1‐/‐ rats during the dark vs. light period (164 ± 40 vs. 306 ± 40 pmol/s*mg; p=0.0031, t‐test). Mitochondrial‐associated genes, optic atrophy 1 (Opal1) and mitofusion 1 (Mfn1) show as significant day‐night difference in mRNA expression in kidneys from BMAL1+/+ control rats that is lost in Bmal1‐/‐ rats consistent with disrupted mitochondrial fusion and fission processes. Our lab previously reported that male Bmal1‐/‐ rats do not have the typical night‐day difference in Na+ excretion, which is consistent with our new data showing an alteration in mitochondrial function in kidneys from Bmal1‐/‐ rats. Therefore, our findings demonstrate that BMAL1 may play a role in maintaining the coupling of mitochondrial respiration and ATP generation in the kidney and support the hypothesis that diurnal Na+handling is regulated in part by BMAL1‐dependent mitochondrial function.

Dysregulation of Skeletal Muscle Mitochondrial Turnover and Dynamics Occurs During Late Symptomatic Stages of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder caused by a mutation in the survival motor neuron 1 (SMN1) gene and it is the leading genetic cause of infant mortality. Recently approved genetic therapies designed to augment full length SMN protein in the central nervous system fail to ameliorate abnormal skeletal muscle features, which strongly suggests an important role for SMN protein in skeletal muscle homeostasis. This study aimed to characterize key modifiers of skeletal muscle mitochondrial turnover and dynamics during disease progression in a pre‐clinical murine model of SMA in vivo. Additionally, we investigated the effects of a single dose of exercise on these mitochondrial biology‐regulating pathways in the skeletal muscle of SMA mice. Muscle samples were collected from wild‐type (WT) and Smn2B/‐ (SMA) mice at postnatal day 9 (P9), P13, and P21 to examine skeletal muscle‐specific disease progression. Mitochondrial content did not differ between genotypes at all timepoints as evident by similar levels of mitochondrial oxidative phosphorylation proteins, succinate dehydrogenase staining, and citrate synthase content. However, mRNA content of key genes responsible for regulating mitochondrial quality such as nuclear respiratory factor 2, mitochondrial transcription factor A, and p53 were significantly higher in SMA mice versus WT at P21. Additionally, we observed elevated mitochondrial fission activity as indicated by a 2‐fold increase (p < 0.05) in dynamin related protein 1 (DRP1) activation. Concomitantly, the expression of several mitophagy proteins including BLC2 interacting protein 3, parkin, and PTEN‐induced kinase 1 were significantly increased by 2.9‐, 2.7‐, and 2‐fold, respectively, compared to WT animals at P21. Interestingly, we observed blunted (p < 0.05) inclusion of optic atrophy 1 exon 4b, a key exon in mitochondrial biogenesis, between WT and SMA mice at P21. Acute exercise significantly increased the inhibition of DRP1‐mediated mitochondrial fission activity in the muscles of SMA mice relative to sedentary SMA mice. However, a single exercise dose failed to alter the expression of mitophagy proteins up to three hours after running. Our data demonstrate that skeletal muscle mitochondrial health is compromised in SMA mice due to elevated fission and mitophagy processes. Furthermore, SMA mice display aberrant alternative splicing of Opa1 transcripts that may in turn hinder mitochondrial biogenesis in later disease stages. We also highlight that an acute bout of treadmill running elicits pro‐fusion signaling to potentially improve the mitochondrial reticulum. Collectively, this study is the first to reveal mitochondrial dysfunction in SMA skeletal muscle and outlines signalling associated with mitochondrial plasticity following a single dose of exercise.

Effect of dissipation coefficient of the K coordinate in dynamical modeling of nuclear fission of 178W produced in fusion reaction

In this paper, a stochastic approach based on two-dimensional dynamical model was used to simulate the fission process of the excited compound nucleus [Formula: see text]W produced in [Formula: see text] reaction. In the dynamical calculations, the elongation parameter of the nucleus was used as the first dimension and the projection of the total spin of the compound nucleus onto the symmetry axis, [Formula: see text], considered as the second dimension. The average pre-fission multiplicities of neutron, light charged particles and the total kinetic energy of the fission fragments were calculated for [Formula: see text]W and the results of calculations compared with the experimental data over a wide range of excitation energy. In the dynamical calculations, dissipation was generated through the chaos weighted wall and window friction formula and the dissipation coefficient of [Formula: see text], was considered as a free parameter and its magnitude inferred by fitting measured data on the average pre-fission multiplicities of neutron and proton for the compound nucleus [Formula: see text]W. It was shown that the results of calculations are in good agreement with the experimental data by using the dissipation coefficient of [Formula: see text] in the range [Formula: see text]. It was also shown that the results of calculations with [Formula: see text] provide a better agreement with the experimental data than with a deformation-dependent dissipation coefficient. Furthermore, it was also shown that differences between the results of calculations for the total kinetic energy of the fission fragments calculated by using different values of dissipation coefficient of [Formula: see text] are small.