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Progress in Biophysics and Molecular... Aug 2022Existing theoretical approaches were considered that allow modelling of mitochondrial swelling (MS) dynamics. Simple phenomenological kinetic models were reviewed.... (Review)
Review
Existing theoretical approaches were considered that allow modelling of mitochondrial swelling (MS) dynamics. Simple phenomenological kinetic models were reviewed. Simple and extended biophysical and bioenergetic models that ignore mechanical properties of inner mitochondrial membrane (IMM), and similar models that include these mechanical properties were also reviewed. Limitations of these models we considered, as regards correct modelling of MS dynamics. It was found that simple phenomenological kinetic models have significant limitations, due to dependence of the kinetic parameter values estimated by fitting of the experimental data on the experimental conditions. Additionally, such simple models provide no understanding of the detailed mechanisms behind the MS dynamics, nor of the dynamics of various system parameters during MS. Thus, biophysical and bioenergetic models ignoring IMM mechanical properties can't be used to model the transition between reversible and irreversible MS. However, simple and extended biophysical models that include IMM mechanical properties allow modelling the transition to irreversible swelling. These latter models are still limited due to significantly simplified description of biochemistry, compared to those of bioenergetic models. Finally, a strategy of model development is proposed, towards correct interpretation of the mitochondrial life cycle, including the effects of MS dynamics.
Topics: Energy Metabolism; Kinetics; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling
PubMed: 35447196
DOI: 10.1016/j.pbiomolbio.2022.04.004 -
Biophysical Chemistry Nov 2021Mitochondrial activity as regards ATP production strongly depends on mitochondrial swelling (MS) mode. Therefore, this work analyzes reversible and irreversible MS using...
Mitochondrial activity as regards ATP production strongly depends on mitochondrial swelling (MS) mode. Therefore, this work analyzes reversible and irreversible MS using a detailed biophysical model. The reported model includes mechanical properties of the inner mitochondrial membrane (IMM). The model describes MS dynamics for spherically symmetric, axisymmetric ellipsoidal and general ellipsoidal mitochondria. Mechanical stretching properties of the IMM were described by a second-rank rigidity tensor. The tensor components were estimated by fitting to the earlier reported results of in vitro experiments. The IMM rigidity constant of ca. 0.008 dyn/nm was obtained for linear deformations. The model also included membrane bending effects, which were small compared to those of membrane stretching. The model was also tested by simulation of the earlier reported experimental data and of the system dynamics at different initial conditions, predicting the system behavior. The transition criteria from reversible to irreversible swelling were determined and tested. The presently developed model is applicable directly to the analysis of in vitro experimental data, while additional improvements are necessary before it could be used to describe mitochondrial swelling in vivo. The reported theoretical model also provides an idea of physically consistent mechanism for the permeability transport pore (PTP) opening, which depends on the IMM stretching stress. In the current study, this idea is discussed briefly, but a detailed theoretical analysis of these ideas will be performed later. The currently developed model provides new understanding of the detailed MS mechanism and of the conditions for the transition between reversible and irreversible MS modes. On the other hand, the current model provides useful mathematical tools, that may be successfully used in mitochondrial biophysics research, and also in other applications, predicting the behavior of mitochondria in different conditions of the surrounding media in vitro or cellular cyto(sarco)plasm in vivo. These mathematical tools are based on real biophysical processes occurring in mitochondria. Thus, we note a significant progress in the theoretical approach, which may be used in real biological systems, compared to the earlier reported models. Significance of this study derives from inclusion of IMM mechanical properties, which directly impact the reversible and irreversible mitochondrial swelling dynamics. Reversible swelling corresponds to reversible IMM deformations, while irreversible swelling corresponds to irreversible deformations, with eventual membrane disruption. The IMM mechanical properties are directly dependent on the membrane biochemical composition and structure. The IMM deformationas are induced by osmotic pressure created by the ionic/neutral solute imbalance between the mitochondrial matrix media and the bulk solution in vitro, or cyto(sarco)plasm in vivo. The novelty of the reported model is in the biophysical mechanism detailing ionic and neutral solute transport for a large number of solutes, which were not taken into account in the earlier reported biophysical models of MS. Therefore, the reported model allows understanding response of mitochondria to the changes of initial concentration(s) of any of the solute(s) included in the model. Note that the values of all of the model parameters and kinetic constants have been estimated and the resulting complete model may be used for quantitative analysis of mitochondrial swelling dynamics in conditions of real in vitro experiments.
Topics: Biophysical Phenomena; Calcium; Computer Simulation; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling
PubMed: 34418677
DOI: 10.1016/j.bpc.2021.106668 -
Methods in Molecular Biology (Clifton,... 2022The loss of mitochondrial cristae integrity and mitochondrial swelling are hallmarks of multiple forms of necrotic cell death. One of the most well-studied and relevant...
The loss of mitochondrial cristae integrity and mitochondrial swelling are hallmarks of multiple forms of necrotic cell death. One of the most well-studied and relevant inducers of mitochondrial swelling is matrix calcium (Ca). Respiring mitochondria will intake available Ca into their matrix until a threshold is reached which triggers the opening of the mitochondrial permeability transition pore (MPTP). Upon opening of the pore, mitochondrial membrane potential dissipates and the mitochondria begin to swell, rendering them dysfunctional. The total amount of Ca taken up by a mitochondrion prior to the engagement of the MPTP is referred to as mitochondrial Ca retention capacity (CRC). The CRC/swelling assay is a useful tool for observing the dose-dependent event of mitochondrial dysfunction in real-time. In this technique, isolated mitochondria are treated with specific boluses of Ca until they reach CRC and undergo swelling. A fluorometer is utilized to detect an increase in transmitted light passing through the sample as the mitochondria lose cristae density, and simultaneously measures calcium uptake by way of a Ca-specific membrane impermeable fluorescent dye. Here we provide a detailed protocol describing the mitochondrial CRC/swelling assay and we discuss how varying amounts of mitochondria and Ca added to the system affect the dose-dependency of the assay. We also report how to validate the assay by using MPTP and calcium uptake inhibitors and troubleshooting common mistakes that occur with this approach.
Topics: Calcium; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mitochondrial Swelling; Permeability
PubMed: 35771440
DOI: 10.1007/978-1-0716-2309-1_9 -
Bio Systems Dec 2021An extended biophysical model was obtained by upgrading the previously reported one (Khmelinskii and Makarov, 2021). The upgraded model accommodates variations of solute...
An extended biophysical model was obtained by upgrading the previously reported one (Khmelinskii and Makarov, 2021). The upgraded model accommodates variations of solute transport rates through the inner mitochondrial membrane (IMM) within the mitochondrial population, described by a Gaussian distribution. However, the model may be used for any functional form of the distribution. The dynamics of system parameters as predicted by the current model differed from that predicted by the previous model in the same initial conditions (Khmelinskii and Makarov, 2021). The amount of change varied from one parameter to the other, remaining in the 1-38% range. The upgraded model fitted the available experimental data with a better accuracy (R = 0.993) compared to the previous model (R = 0.978) using the same experimental data (Khmelinskii and Makarov, 2021). The fitting procedure also estimated the Gaussian distribution parameters. The new model requires much larger computational resources, but given its higher accuracy, it may be used for better analysis of experimental data and for better prediction of MS dynamics in different initial conditions. Note that activities of individual mitochondria in mitochondrial populations should vary within biological tissues. Thus, the currently upgraded model is a better tool for biological and bio-medical applications. We believe that this model is much better adapted to the analysis of MS dynamics in vivo.
Topics: Animals; Biophysical Phenomena; Humans; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling; Models, Biological
PubMed: 34627969
DOI: 10.1016/j.biosystems.2021.104559 -
Toxicon : Official Journal of the... Sep 2023Immune system hyperactivation is involved with clinical severity and pathological alterations during scorpion envenomation. In a murine model, mice inoculated with a...
Immune system hyperactivation is involved with clinical severity and pathological alterations during scorpion envenomation. In a murine model, mice inoculated with a lethal dose of Tityus serrulatus scorpion venom presented mitochondrial swelling in cardiomyocytes, with other structures such as sarcomeres and intercalated disks preserved. Treatment with dexamethasone or knockout animals to the interleukin-1β receptor do not undergo mitochondrial changes in cardiomyocytes during envenomation.
Topics: Animals; Mice; Myocytes, Cardiac; Mitochondrial Swelling; Disease Models, Animal; Scorpion Stings; Scorpion Venoms; Scorpions
PubMed: 37595687
DOI: 10.1016/j.toxicon.2023.107259 -
Archives of Gerontology and Geriatrics May 1989The effects of idebenone on the swelling of rat brain mitochondria were studied. When FeCl3 was added to a mitochondrial suspension, a pronounced mitochondrial swelling... (Review)
Review
The effects of idebenone on the swelling of rat brain mitochondria were studied. When FeCl3 was added to a mitochondrial suspension, a pronounced mitochondrial swelling occurred accompanied by the production of lipid peroxide; the two phenomena were closely correlated (r = 0.96, p less than 0.01). Idebenone inhibited the mitochondrial swelling and lipid peroxidation in a concentration-dependent manner; the concentration giving 50% inhibition was 37 microM for swelling and 53 microM for lipid peroxidation. Metabolites of idebenone also inhibited the lipid peroxidation. These results suggest that idebenone stabilizes the mitochondrial membrane by inhibiting lipid peroxidation in brain mitochondria.
Topics: Animals; Benzoquinones; Brain; Dose-Response Relationship, Drug; Lipid Peroxidation; Male; Mitochondrial Swelling; Quinones; Rats; Rats, Inbred Strains; Ubiquinone
PubMed: 2669658
DOI: 10.1016/0167-4943(89)90011-3 -
Bio Systems Jul 2022Theoretical biophysical model is reported for mitochondrial swelling (MS) dynamics in vivo. This newly developed model is based on the detailed biophysical model of MS...
Theoretical biophysical model is reported for mitochondrial swelling (MS) dynamics in vivo. This newly developed model is based on the detailed biophysical model of MS dynamics in vitro, where mechanical properties of the inner mitochondrial membrane (IMM) were taken into account. The present model of MS dynamics in vivo is capable of analyzing MS dynamic transition from the reversible (physiological) to the irreversible (pathological) mode. This model was used to describe myocytes, assuming 1000 mitochondria distributed homogeneously over the sarcoplasm. Solute transport through the myocyte membrane was described by simplified phenomenological mechanisms of solute uptake and release. Biophysical processes occurring in mitochondria within cells were similar to those included in the earlier reported in vitro biophysical model of MS dynamics. Additionally, in vivo MS dynamics was simulated in different initial conditions, with results different from those of the in vitro model. Note that the presently reported model is the first attempt to develop a detailed biophysical model for the analysis of MS dynamics in vivo, capable of reproducing the transition between reversible and irreversible MS dynamics.
Topics: Biophysical Phenomena; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling
PubMed: 35413385
DOI: 10.1016/j.biosystems.2022.104679 -
Journal of Visualized Experiments : JoVE May 2018The production of ATP by oxidative phosphorylation is the primary function of mitochondria. Mitochondria in higher eukaryotes also participate in cytosolic Ca buffering,...
The production of ATP by oxidative phosphorylation is the primary function of mitochondria. Mitochondria in higher eukaryotes also participate in cytosolic Ca buffering, and the ATP production in mitochondrial can be mediated by intramitochondrial free Ca concentration. Ca retention capacity can be regarded as the capability of mitochondria to retain calcium in the mitochondrial matrix. Accumulated intracellular Ca leads to the permeability of the inner mitochondrial membrane, termed the opening of mitochondrial permeability transition pore (mPTP), which leads to the leakage of molecules with a molecular weight less than 1.5 kDa. Ca-triggered mitochondria swelling is used to indicate the mPTP opening. Here, we describe two assays to examine the Ca retention capacity and Ca-triggered mitochondrial swelling in isolated mitochondria. After certain amounts of Ca are added, all steps can be completed in one day and recorded by a microplate reader. Thus, these two simple and effective assays can be adopted to assess the Ca-related mitochondrial functions.
Topics: Biological Assay; Calcium; Humans; Mitochondrial Swelling; Protein Biosynthesis
PubMed: 29781984
DOI: 10.3791/56236 -
Neuroscience May 2013Although mitochondrial dysfunction is intimately related to axonal degeneration following nerve injury, the molecular mechanisms of mitochondrial swelling and its...
Although mitochondrial dysfunction is intimately related to axonal degeneration following nerve injury, the molecular mechanisms of mitochondrial swelling and its mechanistic relation to axonal degeneration are largely unknown. Previous studies have demonstrated that axonal degeneration in the injured peripheral nerves shows two morphologically distinct phases: (1) A latency period (∼24h), in which the morphology of axonal cytoskeletons seems unchanged, followed by (2) an execution period (36-48h), which shows a catastrophic granular degeneration of most axonal structures in rodent axons. In the present study, we found that, in the sciatic nerve axotomy model, energy failure and microtubule depolymerization occurred during the latency period whereas mitochondrial swelling and neurofilament degradation started in the execution period. The energy repletion with NAD or an NAD/pyruvate mixture inhibited microtubule depolymerization, mitochondrial swelling and axonal degeneration in transected sciatic nerve axons. In addition, microtubule perturbing agents enhanced axonal degeneration and mitochondrial swelling. Extracellular calcium chelation did not affect energy failure, microtubule depolymerization or mitochondrial swelling, but it did prevent neurofilament degradation. These findings suggest that an early disturbance in energy dynamics regardless of mitochondrial swelling might be a key trigger for the initiation of axonal degeneration and that extracellular calcium influx is a late effector for neurofilament degradation.
Topics: Animals; Axons; Axotomy; Mice; Mice, Inbred C57BL; Microtubules; Mitochondria; Mitochondrial Swelling; Paclitaxel; Sciatic Nerve; Tubulin Modulators; Vincristine; Wallerian Degeneration
PubMed: 23485808
DOI: 10.1016/j.neuroscience.2013.02.033 -
Experimental Physiology Oct 2013The significance of the reduction of the cholesterol pool in heart mitochondria after exercise is still unknown. Recently, published data have suggested that cholesterol...
The significance of the reduction of the cholesterol pool in heart mitochondria after exercise is still unknown. Recently, published data have suggested that cholesterol may influence the components of mitochondrial contact site and affect mitochondrial swelling. Therefore, the aim of this study was to determine whether the decreased cholesterol content in heart mitochondria caused by prolonged swimming may provoke changes in their bioenergetics and result in an increased resistance to calcium chloride-induced mitochondrial swelling. Male Wistar rats were divided into a sedentary control group and an exercise group. The rats exercised for 3 h, burdened with an additional 3% of their body weight. Their hearts were removed immediately after completing the exercise. The left ventricle was divided and used for experiments. Mitochondrial cholesterol content, membrane fluidity and mitochondrial bioenergetics were measured in the control and exercised rat heart mitochondria. To assess whether mitochondrial modifications are linked to disruption of lipid microdomains, methyl-β-cyclodextrin, a well-known lipid microdomain-disrupting agent and cholesterol chelator, was applied to the mitochondria of the control group. Cholesterol depletion, increased membrane fluidity and increased resistance to calcium chloride-induced swelling were observed in postexercise heart crude mitochondrial fraction. Similar results were achieved in control mitochondria treated with 2% methyl-β-cyclodextrin. All of the mitochondrial bioenergetics parameters were similar between the groups. Therefore, the disruption of raft-like microdomains appears to be an adaptive change in the rat heart following exercise.
Topics: Animals; Calcium Chloride; Cholesterol; Lactic Acid; Male; Membrane Fluidity; Mitochondria, Heart; Mitochondrial Swelling; Oxidative Stress; Physical Conditioning, Animal; Rats; Rats, Wistar; Swimming
PubMed: 23733522
DOI: 10.1113/expphysiol.2013.073007