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Review Article | DOI: https://doi.org/10.31579/2690-8816/059
1 Associate Professor of the Department of Pathological Physiology named after D.A. Maslakov Grodno State Medical University, Rep. Belarus.
2 Grodno State Medical University, 80, Gorkogo St., 230009, Grodno, Republic of Belarus.
*Corresponding Author: Bon Elizaveta I. Associate Professor of the Department of Pathological Physiology named after D.A. Maslakov Grodno State Medical University, Rep. Belarus.
Citation: Bon E. I, Maksimovich N.Ye, Ostrovskaya O.B and Lychkovskaya M.A (2022). Mitochondrial Movement: A Review. J. Clinical Research Notes. 3(3); DOI: 10.31579/2690-8816/059
Copyright: © 2022 Bon Elizaveta I, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 25 February 2022 | Accepted: 10 March 2022 | Published: 01 April 2022
Keywords: mitochondria; genetic diseases; proteins; mitochondrial fusion and division
The balance between fusion and division determines most of the functions of mitochondria, controls their bioenergetic function, mitochondrial turnover, and also protects mitochondrial DNA. The division promotes equal segregation of mitochondria into daughter cells during cell division itself and enhances the distribution of mitochondria along the cytoskeletal pathways. In addition, division can help isolate damaged mitochondrial segments and thus promote autophagy. Fusion provides protein complementation, and equal distribution of metabolites. The movement of mitochondria in the dendrites, axons and perikaryons of neurons is an important aspect of the vital activity of nerve cells. Disorders of mitochondrial fusion, division, and mobility can lead to defects in the functioning of the nervous system, which makes it important to study these processes for improvig methods of prevention, diagnosis, and correction of neurological diseases.
Mitochondria are accumulations of free floating organelles in the cytosol. They are known to be called the "powerhouse" of the cell. The main function of mitochondria is to generate energy in the form of adenosine triphosphate (ATP). Mitochondria play many important biological roles, including ATP production, lipid biogenesis, ROS regulation, and calcium clearance. They are very dynamic and have a very complex structure. Mitochondria are involved in the metabolism of lipids and amino acids [26]. They also store the intermediates of pyruvate and Krebs cycle oxidation and play a role in scavenging free radicals and controlling programmed cell death. The mitochondrial matrix carries 10–100 or more copies of circular mitochondrial DNA [35]. Modern research shows that mitochondria undergo constant morphological changes during continuous cycles of fusion and division, resulting in the formation of mitochondria with different morphologies, from fragmented states to continuous networks [3, 7].
The balance between fusion and division determines most of the functions of mitochondria, it controls their bioenergetic function, mitochondrial turnover, and also protects mitochondrial DNA [24]. Mitochondria can change their shape, ranging from discrete isolated organelles to the shape of a large, continuous reticulum. Mitochondrial dynamics and morphological structures have been the subject of extensive research in the past few decades: they are fundamental to the functioning of the cell, in addition, mitochondria are very sensitive to the cellular state and are involved in numerous diseases, including Parkinson's disease, diabetes, cancer and Alzheimer's disease, as well as play a key role in various mitochondrial diseases [4, 13, 14, 18, 23, 29]. Various effects of mitochondrial fusion states have been observed, including increased energy production, protection from apoptotic stress, increased cell proliferation, and regulation of various signaling pathways. Mitochondria are very important for aerobic cells. Neurons, for example, depend on the function of mitochondria, so a violation of these organelles can cause neurological diseases [30]. This vulnerability is explained by the high metabolic requirements of neurons, their dependence on correct communication with calcium and their susceptibility to local proapoptotic and reactive signaling of oxygen species, processes in which mitochondria are critically involved. Moreover, neurons must coordinate the supply, maintenance, and elimination of mitochondria with the various metabolic demands of the perikaryon, synapses, and neurons. Central to this intracellular homeostasis is microtubule-mediated transport, the impairment of which also manifests itself as neuropathology. It is noted that impairment of the mitochondrial function of neurons is associated with the initiation or enhancement of neuronal damage [7, 18, 26, 27].
Neurons are primarily metabolically active cells that require a lot of energy in places far from the cell body. In this regard, cells are particularly dependent on mitochondrial function, which was reflected in the observation that mitochondrial dysfunction diseases often have a neurodegenerative component. Recent discoveries have shown that neurons are highly dependent on the plastic properties of mitochondria. Type 2A Charcot-Marie-Tooth, peripheral neuropathy and dominant optic atrophy, hereditary optic neuropathy, result from primary mitochondrial fusion deficiency [30]. Moreover, several major neurodegenerative diseases, namely Parkinson's, Alzheimer's and Huntington's disease, are associated with impaired mitochondrial dynamics [4, 5, 7, 11, 13, 14, 23].
Neurons are more extended and complex in shape than other cells, and therefore face a very serious problem in the distribution and maintenance of mitochondria in their branches. Mitochondria need constant rejuvenation, no matter how far from the perikaryon. Axonal transport of mitochondria, as well as mitochondrial division and fusion, contribute to this rejuvenation, while local protein synthesis will also be involved [32]. Maintaining a healthy population of mitochondria requires the removal of damaged proteins and organelles. This includes sequestration in vesicles, degradation of individual proteins derived from mitochondria, degradation of organelles by mitophagy and macroautophagy, and, in some cases, transfer to glial cells. Poetmou, both long-distance transport and local processing, work in achieving mitostasis of neurons: maintaining a properly distributed pool of healthy mitochondria throughout the life of a neuron. Accordingly, defects in the processes that maintain mitostasis contribute significantly to neurodegenerative disorders [6, 10].
Mitochondrial Movement
During development, neurons require a highly integrated metabolic mechanism to meet the enormous energy requirements for growth, differentiation, and synaptic activity in their highly complex cellular structure. Acute depletion of energy will impair mitochondrial dynamics [11, 17, 26, 33].
Since iron deficiency greatly impairs mitochondrial respiration and ATP production, a study was conducted where cultures of hippocampal neurons of mice of different sexes were treated with an iron chelator deferoxamine to simulate chronic energy deficiency and its effect on mitochondrial dynamics during neuronal development [27, 37]. After 11 days in vitro, deferoxamine strongly reduced the mean mitochondrial velocity by increasing the pause rate of individual dendritic mitochondria [11, 17]. The time spent in anterograde movements was reduced, while the retrograde movement, on the contrary, was preserved. From observations of the movement of mitochondria in dendrites and axons in cultured neurons, it is concluded that mitochondria can undergo targeted movement from one destination in the cell to another. The average size of moving mitochondria decreased, and the expression of genes for division was slightly altered, indicating a violation of mitochondrial quality control [33]. The density of mitochondria did not change, which indicates that it is respiratory capacity, rather than localization, that is the key factor in mitochondrial regulation of early growth and branching of dendrites [28]. This study provides new insight into the cross-regulation between energy production and dendritic mitochondrial dynamics during neuronal development and may be important for neuropsychiatric as well as neurodegenerative diseases, many of which are characterized by impaired brain iron homeostasis, energy metabolism, and mitochondrial transport [11, 18, 26, 37].
Regulation of mitochondria occurs through four dynamic processes: fixation, mobility, division and fusion [34]. Mitochondrial movement can be easily assessed by video microscopy of mitochondria that have been fluorescently labeled with either a fluorescent dye such as tetramethylrhodamine or a fluorescent protein intended for import into mitochondria. Note that one population of mitochondria is in motion, while the other is motionless. The difference between these two classes of mitochondria will reflect two different pools: specifically, mobile mitochondria can temporarily stop moving, but they still tend to continue moving forward and will only very rarely change their direction. Thus, it can be concluded that some of the motile mitochondria are specifically designed for anterograde movement down the axon, while others prefer retrograde movement. Interconnected mitochondria will be found in the bodies of nerve cells, but in order to enter the axon, the mitochondrion must first undergo a division reaction that will free it from the reticulum [36]. The division is mediated by a protein, GTPase Drp1, and in almost all cases, contact with the endoplasmic reticulum and actin initiates the process together with the Drp1 receptor MFF is a mitochondrial division factor. When mitochondria meet end-to-end, the opposite fusion reaction is observed [6, 34].
Mechanisms of Movement of Mitochondria
In frogs, in isolated axons, it is indicated that in neurons most of the mitochondria are in motion. In addition, mitochondrial transport will depend on the same microtubules that characterize the axonal transport of other organelles [32]. On the other hand, the detailed characteristics of mitochondrial transport in neurons turned out to be unique: first, there are mitochondria that move in any direction (anterograde and retrograde) with small obvious changes in direction to the middle of the axon [34].
Secondly, there are pauses alternating between phases of stable translocation, which leads to an average speed of 0.25–1 µm/s, which is lower than the average speed of transport of other organelles.
Third, in addition to transport, mitochondria also show other dynamic behavior, fusion and division, which will greatly complicate the analysis of mitochondrial transport, because the identity of a displaced organelle can be removed by interaction with other mitochondria. Thus, in vitro observations were able to paint a step-by-step picture of how the mitochondria of neurons might behave and allowed for fundamental biological and mechanistic analyzes of cells. The good news is that the basic principles of mitochondrial dynamics, obtained as a result of in vitro work, have also been confirmed in vivo [11, 17].
In addition to this in vivo study, many other aspects of this disclosure in vitro have been validated, a number of new questions have been raised, and research has opened up in complex developmental and disease contexts that are virtually impossible to simulate in vitro [30]. It is worth noting that there have been conflicting reports on the extent of mitochondrial movement in vivo. A number of studies have shown that about 10-20% of mitochondria in axons near the neuronal perikaryon move at absolutely any point in time, even under conditions where neuronal activity may either be absent due to surgical isolation, or is suppressed by anesthesia. In general, three models can explain the rejuvenation of the stationary pool:
1) The "changing of the guard" model: stationary mitochondria can collect and leave their sentry stations, perhaps every few weeks, to undergo mitophagy.
2) The "space station" model: They are undergoing rejuvenation by merging with a moving pool in much the same way that delivering rockets from Earth can keep the space station resupplied.
3) The “locally produced” model: mitochondria undergo constant low-level rejuvenation from local sources such as axonal protein synthesis. Of course, all these mechanisms can work in parallel, and only a complex and accurate analysis of the rate of remobilization, fusion and protein synthesis will help determine their contribution [25, 34].
A number of proteins are isolated that can be degraded by proteases, which in turn are found in mitochondria. One of the most important classes for the removal of misfolded and denatured proteins are AAA+ mitochondrial proteases. These barrel-shaped proteases are present in the matrix and in the inner mitochondrial membrane, which faces both the matrix and the intermembrane space. They recognize hydrophobic domains that are exposed on misfolded and oxidized proteins and effectively break down and unwind them. From the neurological phenotypes, the significance of these proteases for the control of the quality of mitochondria associated with mutations in their genes is currently known. Such phenotypes include spastic paraplegia, non-syndromic mental retardation, spinocerebellar and spastic ataxia. In neurons, mitochondrial proteases are usually used for non-mitochondrial quality control, namely, misfolded cytosolic proteins for degradation can also be imported into mitochondria [19].
The Importance of Mitochondrial Movement for Neurons
The axons of the neurons themselves lie quite flat and have a diameter of no more than a micrometer. That is why mitochondria move no further than a plane that will be easily visualized, and as long as the body of the cell itself or the growth cone of an axon can be identified, it will be much easier to distinguish directional movement, and thus to trace and trace the mitochondria at a distance of 100 mm or more. In addition, at the moment when mitochondria form a complex network in almost all types of cells, the mitochondria of axons will be separated from this network. They will be found only in the form of discrete organelles, usually no more than 1-3 mm in length, and in dendrites they tend to be significantly longer than in axons. The areas of the neuron that have the greatest need for the production of mitochondrial ATP, in other words with the greatest energy consumption, in the synapses, are mainly located precisely at the ends of the cell. Most of the mitochondria of myelinated nerves are located in stationary pools in internodes. When mitochondria cross the Ranvier node, electrical activity helps to stop or slow down the movement of these organelles, but with a blockade of electrical activity, everything is different: it increases the mobile fraction. These modulations of movement are a consequence of the change in energy supply, which was caused by the opening of ion channels in the nodes when the action potentials are triggered. Such post-mitotic cells must always be viable, but the lifetime of mitochondrial proteins will be much shorter, amounting to only a few weeks. We conclude that a continuous circulation of mitochondria should take place throughout the cell, including the removal of old and damaged components, as well as the delivery of new materials, most of which are encoded by nuclear genes. This process will be facilitated by three stages [20, 27, 37].
The first is the constant movement of mitochondria in both axons and dendrites [37]. A very important feature of mitochondria in axons is that they distinguish between three classes: those that move mainly anterograde (15%), those that move mainly retrograde (15%), and those that seem to be motionless for a long time period (70%). One half will move anterograde (away from the cell body), and the other half will move retrograde (toward the cell body). This movement probably reflects the main mechanism of exchange and delivery of newly synthesized mitochondrial components. We turn to the second factor, which is designed to maintain peripheral mitochondria - this is the division and fusion of mitochondria itself. The fact that such processes can occur not only in axons and dendrites, but also in all cells, boils down to the fact that they allow the exchange of materials also between mitochondria. Even very minor contacts can involve fusion and extensive exchange with proteins in every mitochondrial compartment, as has been visualized in non-neuronal cells [27]. Consequently, mitochondria may well be renewed in their place due to exchange with proteins that have a mobile fraction, although at first glance they seemed completely immobile. There would be no fusion at all, or it would be insignificant if mitochondrial movement was absent, and this is in fact the case. Mitochondria that are actively moving have a higher fusion rate than stationary mitochondria, and the mechanisms of movement and fusion can generally be linked mechanically. The third factor is the presence of local mitochondrial biogenesis in addition to what happens in the body of the cell itself. Local biogenesis of mitochondria helps maintain the health of mitochondria in axons and dendrites. Moreover, local biogenesis can instantly respond to both local changes and those caused either by increased demand or by damage to mitochondria [34, 37].
The regulation and maintenance of cellular metabolism is a critical issue for the nervous system.
The metabolic costs that are aimed at performing and maintaining basic nerve functions are incredibly high, primarily due to the very complex morphology of neurons, and specifically because of their difficultly regulated transmembrane ion gradients and in particular their constant synapse activity. The human brain is one of the most energy-consuming organs, accounting for approximately 20% of the total energy expenditure. Metabolic homeostasis of the brain involves the activation of metabolism in neurons and glia, which together form a metabolic component to meet all the energy needs of neurons, neural processes. Neural circuits are highly dependent on mitochondrial respiration; it is known that other metabolic pathways also contribute to the bioenergetics of neurons, including glycolysis of neurons [24, 26]. Recently, research has been carried out using the latest techniques, such as optogenetics and real-time metabolic imaging, that have identified the pleiotropic roles of mitochondria ranging from nervous system development to neurodegeneration. These organelles, which were originally recognized as the cell's energy source for ATP production through oxidative phosphorylation, play one of the most important roles in calcium clearance, lipid biogenesis, and ROS regulation [35]. Mitochondria found in mature neurons contribute to synaptic transmission and plasticity through local ATP uptake and calcium buffering. But other types of brain cells, in particular glial cells, also supply important energy metabolites to neurons for nourishing synapses, and their apparent increased metabolic plasticity makes them ideal for regulating multiple forms of interaction not only with neurons, but also with the vasculature [26]. Therefore, we can confidently say that mitochondrial dysfunction and altered mitochondrial dynamics are widely observed in various conditions, from impaired neuronal development to various neurodegenerative diseases [11, 27, 31].
It is known that mitochondrial proteins constitute an important part of locally synthesized proteins in neurons. For example, transcriptome analysis of the synaptic neuropil has shown that many of the dendritically localized mRNA transcripts encode mitochondrial proteins of nuclear origin. Interestingly, cortical neurons exhibit distinct mitochondrial morphology in their dendrites and axons. In dendrites, mitochondria have a more elongated shape, overlapping with a high density, while in axons, mitochondria are rather identical small separate units localized in certain positions [17].
Aware of the high energy requirements of our brains, early research focused on identifying the neural mechanisms that make up most of its energy load. Theoretical calculations have shown that ion homeostasis after the propagation of the action potential is the largest consumer of energy. Due to the high energy consumption for synaptic activity, the mechanisms that carry out the local synthesis of ATP are of particular importance for synaptic function. The use of the previously discussed ATP biosensors in combination with pharmacological manipulations has shown that the generation of ATP in neurons is largely due to the activity-dependent absorption of glucose, which is metabolized both by glycolysis and by oxidative phosphorylation in presynaptic terminals. In dendritic spines, mitochondrial ATP synthesis, rather than glycolysis, mainly feeds protein synthesis-dependent synaptic plasticity. Local dysfunction of mitochondria disrupts both local protein synthesis and morphological plasticity of the spine. These studies only confirm the importance of mitochondria in the production of ATP at synapses [20, 31, 37]. However, the molecular mechanisms that induce mitochondrial ATP synthesis in response to local synaptic activity are still relatively poorly understood [11, 17, 26].
Fusion of Mitochondria
It is important to mention the proteins involved in the fusion of mammalian mitochondria, there are only three of them, these are GTPases Optic Atrophy 1 (OPA1) and two mitofusins, MFN1 and MFN2. In mitochondrial division, the central protein is a highly conserved protein that is associated with dynamin 1 (Drp1); it also belongs to the family of large GTPases [5, 12, 21, 24].
It is fusion that allows the exchange of mitochondrial components between damaged and healthy mitochondria to mitigate the effects of cellular stressors. Mitochondrial division and fusion are important for the vitality of neuronal mitochondria. Mitofusin mutations cause peripheral neuropathy, and also cause a permanent decrease in mitochondrial DNA preservation and membrane potential. The fusion provides protein complementation, mtDNA repair, and equal distribution of metabolites [1, 15, 26]. Mitochondrial fusion can increase ATP production through several possible mechanisms. The following possible mechanisms of particular interest are: 1) high ATP is caused by fusion-induced changes in the shape of the inner membrane; 2) high ATP is caused by a decrease in proton leakage caused by fusion; 3) high ATP is caused by a decrease in mitochondrial degradation caused by fusion; 4) high ATP is caused by a non-linear response of the rate of ATP synthesis to the membrane potential. We would like to note that the assumption made in all the above hypotheses boils down to the fact that the fusion causes a very high ATP. But it remains to be seen whether mitochondrial fusion is the cause of the geometric increase in ATP, or whether this hyperfusion and high ATP concentrations have a common cause, for example, a recent study showed that an increase in ATP production in general can be observed earlier than mitochondrial fusion [9, 21, 34, 41].
Mitochondrial Fusion Diseases: Fusion Phenotypes
It is for the maintenance of mitochondrial function that fusion and division factors are extremely important. Division, it is assumed, during cell division, promotes equal segregation of mitochondria into daughter cells and enhances the distribution of mitochondria along the cytoskeletal pathways [34]. In addition, it is division that can help isolate damaged mitochondrial segments and thus contribute to their autophagy. In the event that these defense mechanisms do not work, it is mitochondrial division that can promote apoptosis [10, 18]. Mitophagy refers to the degradation of mitochondria through autophagy [6].
Autophagy is a process by which cellular components are destroyed as a result of absorption by autophagosomes. Autophagosomes fuse with lysosomes, which in turn contain hydrolytic enzymes that break down cellular components. During nutrient deficiencies, foods are processed into more essential molecules [10].
Several recent discoveries show that mitophagy can selectively destroy defective mitochondria. From basic autophagy in yeast cells, mitophagy is regulated independently [6, 10].
Mitostasis in Neurons
Neurons often face problems due to their special structure. Long and very branched processes have developed in neurons between the regions of the central nervous system, to and from peripheral organs, this mechanism works for the rapid transmission of electrical signals. It has been established that in humans, peripheral nerves and cortical-spinal tracts can have axons a meter or more in length [38]. Moreover, since information processing requires extensive convergence and decoding of signals, the cytoplasmic volume of highly branched branches, in this position, easily displaces the volume of the neuronal cell body [27]. Neurons are not dividing cells and therefore must be preserved throughout a person's life. The difference between cellular and protein metabolism is especially great. Note that, as in any cell, almost all neuronal proteins are encoded by genes in the nucleus, and this does not depend on how far this nucleus can be from the site of protein action. Mitostasis is a special form of homeostasis, it is a kind of mechanism by which the number of mitochondria is maintained throughout the entire time in each section of the neuron. How is mitostasis achieved? It is known that the mitochondrial DNA of vertebrates encodes no more than 13 proteins, and the rest of the more than a thousand proteins found in mitochondria are encoded exclusively in the nucleus. Since every part of the neuron needs ATP and therefore requires the obligatory presence of mitochondria. Consequently, some mitochondria need to be retained in the perikaryon, while other mitochondria need to be transported and then positioned along axons and dendrites. This is achieved in order to concentrate in energy-intensive areas, for example in presynaptic terminals and near Ranvier nodes [37]. That is why the transport of mitochondria is a difficult task for the neuron: the balance between supply and demand for energy requires special attention to the needs of each area of the neuron [20].
Study of human TRAK1 isoforms causes fatal lencephalopathy. Parkinson's disease is the most common mitostatic disease identified to date. Several forms of familial Parkinson's disease arise from mutations in PINK1 and Parkin, which in turn alter mitochondrial clearance. At the same time, the study of toxins that cause parkinsonism, such as MPTP+ and rotenone, points to a theory about the mitochondrial origin of the disease [29]. Obtained from the study of mitophagy in neurons showed that a slowdown in Miro degradation and, as a consequence, an inability to stop mitochondria, was typical of many cellular movements derived from this disease. That is, it turned out to be typical not only for those with PINK1 and Parkin mutations. This included LRRK2 mutations and controversial cases of unidentified genetic linkage [2, 6, 8]. Parkinson's disease demonstrates the complexity of the relationship between mitochondrial movement and mitochondrial clearance. Adequate mitochondrial movement in healthy cells maintains the axon pool, but if transport is impaired or mitochondrial health is impaired, mitochondrial movement will be significantly reduced [30, 37]. Thus, the condition of the mitochondria can be further affected. But the constant movement of damaged mitochondria in the neurons of Parkinson's disease and the subsequent proliferation of ROS can do as much harm to the cell as insufficient movement [4, 13]. Moreover, spurious activation of the PINK1 Parkin pathway in a healthy context of mitochondrial arrest can be just as dangerous. Mitochondria are also implicated in many other diseases such as Alzheimer's disease, amyotrophic lateral sclerosis and motor neuron diseases, and of course in conditions where bioenergetic substrates are absent, such as hypoxia and stroke [29]. Altered mitochondria are present in neuroinflammatory lesions. In vivo imaging in disease models demonstrates a decrease in mitochondrial transport, which leads to local accumulation of dysfunctional mitochondria and their lack in distal axons [1, 14, 15, 18].
Disease-causing proteins and mitochondrial transport.
Literally every year, more and more new evidence appears that it is proteins that are associated with neurodegenerative diseases that can affect the axonal transport of organelles in general and mitochondria in particular. The mechanism by which this can happen is characterized by the formation of aggregates in neuronal processes that block transport [27, 32]. A good example of this mechanism would be neurons that express extended polyglutamine forms of huntingtin, a protein that is responsible for Huntington's disease. The disease is autosomal dominant, characterized by a combination of progressive choreic hyperkinesis with mental disorders. In these neurons, the aggregates were associated with mitochondria, and the areas of the neurite around the aggregate showed a small, but very noticeable movement of mitochondria. The slow delivery of mitochondria to sites of demand for ATP, which are distant from the aggregated blocked process, provides a mechanism to explain the slowly developing loss of function of neurons in the striatum, which is precisely associated with this disease [27]. Amyotrophic lateral sclerosis, in contrast to Huntington's disease, is largely a sporadic disease [5, 18]. However, the disease was well modeled in mice by overexpression of mutant forms of copper and zinc superoxide dismutase (mtSOD1), which has been identified in less common familial forms of the disease [25]. Deep mitochondrial defects were observed in neurons that emanate from mtSOD1-expressing mice, which coincided with the emergence of motor neuron pathology. In addition, there is evidence of a decrease in mitochondrial penetration into axons beyond the initial segment, as well as a significant decrease in retrograde mitochondrial transport in motor neuron axons from studies in mtSOD1 mice. It is noted that it is mutant SOD1 that will be associated with mitochondria, and it is possible that this disrupts the interaction of mitochondria with motor proteins or their adapters. Like mtHtt, mtSOD1 is also merged, allowing for physical obstruction. It is important to consider that metabolic dysfunction may be a key event, so that impaired ATP delivery to the motors will be implicated in movement cessation [16, 26]. The microtubule-bound tau protein, when hyperphosphorylated, forms neurofibrillary tangles, which are precisely the main distinguishing and visible sign of Alzheimer's disease [30]. The tau protein also has an important effect on mitochondrial movement. Tau inhibits the attachment of weights to kinesin-based motors, so that overexpression of tau leads to accumulation of mitochondria near the minus end of the microtubules in the center of the cell [14, 16, 18].
When abnormalities in mitochondrial fusion, division, mobility and renewal occur, it can lead to characteristic defects in neurons. Note that these defects also overlap significantly, since these four processes are highly interdependent [11, 34].
The process of transferring mitochondria to distant sites that require extremely high energy consumption is a critical component of both normal neurophysiology and pathophysiology, neurodevelopmental disorders and neurodegenerative disorders. Simultaneously with the development of neurons, mitochondria are attracted to the areas of growth and branching of dendrites, as well as to the formation of spines. Violation of this movement will disrupt dendritic branching and, accordingly, the formation of synapses, which in turn will lead to structural abnormalities [29].
As a rule, mitochondria mainly move along microtubules using ATPase-dependent kinesin and dynein motor proteins, as well as dendritic and axon-specific adapter proteins. Note that the anterograde movement of mitochondrial axons is generated by kinesins. Of the large number of possible kinesin families, it is kinesin-1 and kinesin-3 that make a huge contribution to the movement of mitochondria. Kinesins provide anterograde transport, while dyneins provide retrograde transport. In proximal dendrites, the polarity of microtubules is mixed, and motor proteins are not selective for any of the presented transports [6, 11, 26, 37].
Neurons depend on mitochondrial transport for their survival much more than any other type of cell. Recent research has identified a motor adapter complex on the surface of mitochondria that is common between neurons and other animal cells. In addition to kinesin and dynein, this complex contains the proteins Miro (also known as RhoT1 2) and milton (called TRAK1 2), which are responsible for the movement of mitochondria. The identification of this complex gave an idea of how exactly this movement is regulated by a huge number of intracellular signals. Regulation of mitochondrial movement can cover and fully meet the energy needs to supply all the unusual architecture of these cells, and can also control the replenishment of mitochondria in the periphery and their cleansing [22].
The movement of mitochondria in the dendrites, axons and perikaryons of neurons is an important aspect of the vital activity of nerve cells. Disorders of mitochondrial fusion, division, and mobility can lead to defects in the functioning of the nervous system, which makes it important to study these processes for improving methods of prevention, diagnosis, and correction of neurological diseases.
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"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.
Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.
Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”
Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner
My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.
My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.
My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.
I would like to offer my testimony in the support. I have received through the peer review process and support the editorial office where they are to support young authors like me, encourage them to publish their work in your esteemed journals, and globalize and share knowledge globally. I really appreciate your journal, peer review, and editorial office.
Dear Agrippa Hilda- Editorial Coordinator of Journal of Neuroscience and Neurological Surgery, "The peer review process was very quick and of high quality, which can also be seen in the articles in the journal. The collaboration with the editorial office was very good."
I would like to express my sincere gratitude for the support and efficiency provided by the editorial office throughout the publication process of my article, “Delayed Vulvar Metastases from Rectal Carcinoma: A Case Report.” I greatly appreciate the assistance and guidance I received from your team, which made the entire process smooth and efficient. The peer review process was thorough and constructive, contributing to the overall quality of the final article. I am very grateful for the high level of professionalism and commitment shown by the editorial staff, and I look forward to maintaining a long-term collaboration with the International Journal of Clinical Case Reports and Reviews.
To Dear Erin Aust, I would like to express my heartfelt appreciation for the opportunity to have my work published in this esteemed journal. The entire publication process was smooth and well-organized, and I am extremely satisfied with the final result. The Editorial Team demonstrated the utmost professionalism, providing prompt and insightful feedback throughout the review process. Their clear communication and constructive suggestions were invaluable in enhancing my manuscript, and their meticulous attention to detail and dedication to quality are truly commendable. Additionally, the support from the Editorial Office was exceptional. From the initial submission to the final publication, I was guided through every step of the process with great care and professionalism. The team's responsiveness and assistance made the entire experience both easy and stress-free. I am also deeply impressed by the quality and reputation of the journal. It is an honor to have my research featured in such a respected publication, and I am confident that it will make a meaningful contribution to the field.
"I am grateful for the opportunity of contributing to [International Journal of Clinical Case Reports and Reviews] and for the rigorous review process that enhances the quality of research published in your esteemed journal. I sincerely appreciate the time and effort of your team who have dedicatedly helped me in improvising changes and modifying my manuscript. The insightful comments and constructive feedback provided have been invaluable in refining and strengthening my work".
I thank the ‘Journal of Clinical Research and Reports’ for accepting this article for publication. This is a rigorously peer reviewed journal which is on all major global scientific data bases. I note the review process was prompt, thorough and professionally critical. It gave us an insight into a number of important scientific/statistical issues. The review prompted us to review the relevant literature again and look at the limitations of the study. The peer reviewers were open, clear in the instructions and the editorial team was very prompt in their communication. This journal certainly publishes quality research articles. I would recommend the journal for any future publications.
Dear Jessica Magne, with gratitude for the joint work. Fast process of receiving and processing the submitted scientific materials in “Clinical Cardiology and Cardiovascular Interventions”. High level of competence of the editors with clear and correct recommendations and ideas for enriching the article.
We found the peer review process quick and positive in its input. The support from the editorial officer has been very agile, always with the intention of improving the article and taking into account our subsequent corrections.
My article, titled 'No Way Out of the Smartphone Epidemic Without Considering the Insights of Brain Research,' has been republished in the International Journal of Clinical Case Reports and Reviews. The review process was seamless and professional, with the editors being both friendly and supportive. I am deeply grateful for their efforts.
To Dear Erin Aust – Editorial Coordinator of Journal of General Medicine and Clinical Practice! I declare that I am absolutely satisfied with your work carried out with great competence in following the manuscript during the various stages from its receipt, during the revision process to the final acceptance for publication. Thank Prof. Elvira Farina
Dear Jessica, and the super professional team of the ‘Clinical Cardiology and Cardiovascular Interventions’ I am sincerely grateful to the coordinated work of the journal team for the no problem with the submission of my manuscript: “Cardiometabolic Disorders in A Pregnant Woman with Severe Preeclampsia on the Background of Morbid Obesity (Case Report).” The review process by 5 experts was fast, and the comments were professional, which made it more specific and academic, and the process of publication and presentation of the article was excellent. I recommend that my colleagues publish articles in this journal, and I am interested in further scientific cooperation. Sincerely and best wishes, Dr. Oleg Golyanovskiy.
Dear Ashley Rosa, Editorial Coordinator of the journal - Psychology and Mental Health Care. " The process of obtaining publication of my article in the Psychology and Mental Health Journal was positive in all areas. The peer review process resulted in a number of valuable comments, the editorial process was collaborative and timely, and the quality of this journal has been quickly noticed, resulting in alternative journals contacting me to publish with them." Warm regards, Susan Anne Smith, PhD. Australian Breastfeeding Association.
Dear Jessica Magne, Editorial Coordinator, Clinical Cardiology and Cardiovascular Interventions, Auctores Publishing LLC. I appreciate the journal (JCCI) editorial office support, the entire team leads were always ready to help, not only on technical front but also on thorough process. Also, I should thank dear reviewers’ attention to detail and creative approach to teach me and bring new insights by their comments. Surely, more discussions and introduction of other hemodynamic devices would provide better prevention and management of shock states. Your efforts and dedication in presenting educational materials in this journal are commendable. Best wishes from, Farahnaz Fallahian.
Dear Maria Emerson, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews, Auctores Publishing LLC. I am delighted to have published our manuscript, "Acute Colonic Pseudo-Obstruction (ACPO): A rare but serious complication following caesarean section." I want to thank the editorial team, especially Maria Emerson, for their prompt review of the manuscript, quick responses to queries, and overall support. Yours sincerely Dr. Victor Olagundoye.
Dear Ashley Rosa, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews. Many thanks for publishing this manuscript after I lost confidence the editors were most helpful, more than other journals Best wishes from, Susan Anne Smith, PhD. Australian Breastfeeding Association.
Dear Agrippa Hilda, Editorial Coordinator, Journal of Neuroscience and Neurological Surgery. The entire process including article submission, review, revision, and publication was extremely easy. The journal editor was prompt and helpful, and the reviewers contributed to the quality of the paper. Thank you so much! Eric Nussbaum, MD
Dr Hala Al Shaikh This is to acknowledge that the peer review process for the article ’ A Novel Gnrh1 Gene Mutation in Four Omani Male Siblings, Presentation and Management ’ sent to the International Journal of Clinical Case Reports and Reviews was quick and smooth. The editorial office was prompt with easy communication.
Dear Erin Aust, Editorial Coordinator, Journal of General Medicine and Clinical Practice. We are pleased to share our experience with the “Journal of General Medicine and Clinical Practice”, following the successful publication of our article. The peer review process was thorough and constructive, helping to improve the clarity and quality of the manuscript. We are especially thankful to Ms. Erin Aust, the Editorial Coordinator, for her prompt communication and continuous support throughout the process. Her professionalism ensured a smooth and efficient publication experience. The journal upholds high editorial standards, and we highly recommend it to fellow researchers seeking a credible platform for their work. Best wishes By, Dr. Rakhi Mishra.
