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1
Elizaveta, Bon. "Mitochondrial Movement: A Review". Clinical Research Notes 3, n. 3 (30 aprile 2022): 01–06. http://dx.doi.org/10.31579/2690-8816/059.
Abstract (sommario):
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.
2
Delmotte, Philippe, Vanessa A. Zavaletta, Michael A. Thompson, Y. S. Prakash e Gary C. Sieck. "TNFα decreases mitochondrial movement in human airway smooth muscle". American Journal of Physiology-Lung Cellular and Molecular Physiology 313, n. 1 (1 luglio 2017): L166—L176. http://dx.doi.org/10.1152/ajplung.00538.2016.
Abstract (sommario):
In airway smooth muscle (ASM) cells, excitation-contraction coupling is accomplished via a cascade of events that connect an elevation of cytosolic Ca2+ concentration ([Ca2+]cyt) with cross-bridge attachment and ATP-consuming mechanical work. Excitation-energy coupling is mediated by linkage of the elevation of [Ca2+]cyt to an increase in mitochondrial Ca2+ concentration, which in turn stimulates ATP production. Proximity of mitochondria to the sarcoplasmic reticulum (SR) and plasma membrane is thought to be an important mechanism to facilitate mitochondrial Ca2+ uptake. In this regard, mitochondrial movement in ASM cells may be key in establishing proximity. Mitochondria also move where ATP or Ca2+ buffering is needed. Mitochondrial movement is mediated through interactions with the Miro-Milton molecular complex, which couples mitochondria to kinesin motors at microtubules. We examined mitochondrial movement in human ASM cells and hypothesized that, at basal [Ca2+]cyt levels, mitochondrial movement is necessary to establish proximity of mitochondria to the SR and that, during the transient increase in [Ca2+]cyt induced by agonist stimulation, mitochondrial movement is reduced, thereby promoting transient mitochondrial Ca2+ uptake. We further hypothesized that airway inflammation disrupts basal mitochondrial movement via a reduction in Miro and Milton expression, thereby disrupting the ability of mitochondria to establish proximity to the SR and, thus, reducing transient mitochondrial Ca2+ uptake during agonist activation. The reduced proximity of mitochondria to the SR may affect establishment of transient “hot spots” of higher [Ca2+]cyt at the sites of SR Ca2+ release that are necessary for mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter.
3
Gurdon, Csanad, Zora Svab, Yaping Feng, Dibyendu Kumar e Pal Maliga. "Cell-to-cell movement of mitochondria in plants". Proceedings of the National Academy of Sciences 113, n. 12 (7 marzo 2016): 3395–400. http://dx.doi.org/10.1073/pnas.1518644113.
Abstract (sommario):
We report cell-to-cell movement of mitochondria through a graft junction. Mitochondrial movement was discovered in an experiment designed to select for chloroplast transfer from Nicotiana sylvestris into Nicotiana tabacum cells. The alloplasmic N. tabacum line we used carries Nicotiana undulata cytoplasmic genomes, and its flowers are male sterile due to the foreign mitochondrial genome. Thus, rare mitochondrial DNA transfer from N. sylvestris to N. tabacum could be recognized by restoration of fertile flower anatomy. Analyses of the mitochondrial genomes revealed extensive recombination, tentatively linking male sterility to orf293, a mitochondrial gene causing homeotic conversion of anthers into petals. Demonstrating cell-to-cell movement of mitochondria reconstructs the evolutionary process of horizontal mitochondrial DNA transfer and enables modification of the mitochondrial genome by DNA transmitted from a sexually incompatible species. Conversion of anthers into petals is a visual marker that can be useful for mitochondrial transformation.
4
E.I,, Bon. "Mechanisms of Movement of Mitochondria in the Cell". Clinical Endocrinology and Metabolism 1, n. 1 (26 ottobre 2022): 01–06. http://dx.doi.org/10.31579/2834-8761/005.
Abstract (sommario):
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 improving methods of prevention, diagnosis, and correction of neurological diseases.
5
Yi, Muqing, David Weaver e György Hajnóczky. "Control of mitochondrial motility and distribution by the calcium signal". Journal of Cell Biology 167, n. 4 (15 novembre 2004): 661–72. http://dx.doi.org/10.1083/jcb.200406038.
Abstract (sommario):
Mitochondria are dynamic organelles in cells. The control of mitochondrial motility by signaling mechanisms and the significance of rapid changes in motility remains elusive. In cardiac myoblasts, mitochondria were observed close to the microtubular array and displayed both short- and long-range movements along microtubules. By clamping cytoplasmic [Ca2+] ([Ca2+]c) at various levels, mitochondrial motility was found to be regulated by Ca2+ in the physiological range. Maximal movement was obtained at resting [Ca2+]c with complete arrest at 1–2 μM. Movement was fully recovered by returning to resting [Ca2+]c, and inhibition could be repeated with no apparent desensitization. The inositol 1,4,5-trisphosphate– or ryanodine receptor-mediated [Ca2+]c signal also induced a decrease in mitochondrial motility. This decrease followed the spatial and temporal pattern of the [Ca2+]c signal. Diminished mitochondrial motility in the region of the [Ca2+]c rise promotes recruitment of mitochondria to enhance local Ca2+ buffering and energy supply. This mechanism may provide a novel homeostatic circuit in calcium signaling.
6
Kaasik, Allen, Dzhamilja Safiulina, Alexander Zharkovsky e Vladimir Veksler. "Regulation of mitochondrial matrix volume". American Journal of Physiology-Cell Physiology 292, n. 1 (gennaio 2007): C157—C163. http://dx.doi.org/10.1152/ajpcell.00272.2006.
Abstract (sommario):
Mitochondrial volume homeostasis is a housekeeping cellular function essential for maintaining the structural integrity of the organelle. Changes in mitochondrial volume have been associated with a wide range of important biological functions and pathologies. Mitochondrial matrix volume is controlled by osmotic balance between cytosol and mitochondria. Any dysbalance in the fluxes of the main intracellular ion, potassium, will thus affect the osmotic balance between cytosol and the matrix and promote the water movement between these two compartments. It has been hypothesized that activity of potassium efflux pathways exceeds the potassium influx in functioning mitochondria and that potassium concentration in matrix could be actually lower than in cytoplasm. This hypothesis provides a clear-cut explanation for the mitochondrial swelling observed after mitochondrial depolarization, mitochondrial calcium overload, or opening of permeability transition pore. It should also be noted that the rate of water flux into or out of the mitochondrion is determined not only by the osmotic gradient that acts as the driving force for water transport but also by the water permeability of the inner membrane. Recent data suggest that the mitochondrial inner membrane has also specific water channels, aquaporins, which facilitate water movement between cytoplasm and matrix. This review discusses different phases of mitochondrial swelling and summarizes the potential effects of mitochondrial swelling on cell function.
7
Simon, V. R., T. C. Swayne e L. A. Pon. "Actin-dependent mitochondrial motility in mitotic yeast and cell-free systems: identification of a motor activity on the mitochondrial surface." Journal of Cell Biology 130, n. 2 (15 luglio 1995): 345–54. http://dx.doi.org/10.1083/jcb.130.2.345.
Abstract (sommario):
Using fluorescent membrane potential sensing dyes to stain budding yeast, mitochondria are resolved as tubular organelles aligned in radial arrays that converge at the bud neck. Time-lapse fluorescence microscopy reveals region-specific, directed mitochondrial movement during polarized yeast cell growth and mitotic cell division. Mitochondria in the central region of the mother cell move linearly towards the bud, traverse the bud neck, and progress towards the bud tip at an average velocity of 49 +/- 21 nm/sec. In contrast, mitochondria in the peripheral region of the mother cell and at the bud tip display significantly less movement. Yeast strains containing temperature sensitive lethal mutations in the actin gene show abnormal mitochondrial distribution. No mitochondrial movement is evident in these mutants after short-term shift to semi-permissive temperatures. Thus, the actin cytoskeleton is important for normal mitochondrial movement during inheritance. To determine the possible role of known myosin genes in yeast mitochondrial motility, we investigated mitochondrial inheritance in myo1, myo2, myo3 and myo4 single mutants and in a myo2, myo4 double mutant. Mitochondrial spatial arrangement and motility are not significantly affected by these mutations. We used a microfilament sliding assay to examine motor activity on isolated yeast mitochondria. Rhodamine-phalloidin labeled yeast actin filaments bind to immobilized yeast mitochondria, as well as unilamellar, right-side-out, sealed mitochondrial outer membrane vesicles. In the presence of low levels of ATP (0.1-100 microM), we observed F-actin sliding on immobilized yeast mitochondria. In the presence of high levels of ATP (500 microM-2 mM), bound filaments are released from mitochondria and mitochondrial outer membranes. The maximum velocity of mitochondria-driven microfilament sliding (23 +/- 11 nm/sec) is similar to that of mitochondrial movement in living cells. This motor activity requires hydrolysis of ATP, does not require cytosolic extracts, is sensitive to protease treatment, and displays an ATP concentration dependence similar to that of members of the myosin family of actin-based motors. This is the first demonstration of an actin-based motor activity in a defined organelle population.
8
Förtsch, Johannes, Eric Hummel, Melanie Krist e Benedikt Westermann. "The myosin-related motor protein Myo2 is an essential mediator of bud-directed mitochondrial movement in yeast". Journal of Cell Biology 194, n. 3 (1 agosto 2011): 473–88. http://dx.doi.org/10.1083/jcb.201012088.
Abstract (sommario):
The inheritance of mitochondria in yeast depends on bud-directed transport along actin filaments. It is a matter of debate whether anterograde mitochondrial movement is mediated by the myosin-related motor protein Myo2 or by motor-independent mechanisms. We show that mutations in the Myo2 cargo binding domain impair entry of mitochondria into the bud and are synthetically lethal with deletion of the YPT11 gene encoding a rab-type guanosine triphosphatase. Mitochondrial distribution defects and synthetic lethality were rescued by a mitochondria-specific Myo2 variant that carries a mitochondrial outer membrane anchor. Furthermore, immunoelectron microscopy revealed Myo2 on isolated mitochondria. Thus, Myo2 is an essential and direct mediator of bud-directed mitochondrial movement in yeast. Accumulating genetic evidence suggests that maintenance of mitochondrial morphology, Ypt11, and retention of mitochondria in the bud contribute to Myo2-dependent inheritance of mitochondria.
9
Finsterer, J., e S. Zarrouk-Mahjoub. "Mitochondrial movement disorders". Revue Neurologique 172, n. 11 (novembre 2016): 716–17. http://dx.doi.org/10.1016/j.neurol.2016.09.002.
10
Beltran-Parrazal, Luis, Héctor E. López-Valdés, K. C. Brennan, Mauricio Díaz-Muñoz, Jean de Vellis e Andrew C. Charles. "Mitochondrial transport in processes of cortical neurons is independent of intracellular calcium". American Journal of Physiology-Cell Physiology 291, n. 6 (dicembre 2006): C1193—C1197. http://dx.doi.org/10.1152/ajpcell.00230.2006.
Abstract (sommario):
Mitochondria show extensive movement along neuronal processes, but the mechanisms and function of this movement are not clearly understood. We have used high-resolution confocal microscopy to simultaneously monitor movement of mitochondria and changes in intracellular [Ca2+] ([Ca2+]i) in rat cortical neurons. A significant percentage (27%) of the total mitochondria in cortical neuronal processes showed movement over distances of >2 μM. The average velocity was 0.52 μm/s. The velocity, direction, and pattern of mitochondrial movement were not affected by transient increases in [Ca2+]i associated with spontaneous firing of action potentials. Stimulation of Ca2+ transients with forskolin (10 μM) or bicuculline (10 μM), or sustained elevations of [Ca2+]i evoked by glutamate (10 μM) also had no effect on mitochondrial transit. Neither removal of extracellular Ca2+, depletion of intracellular Ca2+ stores with thapsigargin, or inhibition of synaptic activity with TTX (1 μM) or a cocktail of CNQX (10 μM) and MK801 (10 μM) affected mitochondrial movement. These results indicate that movement of mitochondria along processes is a fundamental activity in neurons that occurs independently of physiological changes in [Ca2+]i associated with action potential firing, synaptic activity, or release of Ca2+ from intracellular stores.
11
Taylor, Dale F., e David J. Bishop. "Transcription Factor Movement and Exercise-Induced Mitochondrial Biogenesis in Human Skeletal Muscle: Current Knowledge and Future Perspectives". International Journal of Molecular Sciences 23, n. 3 (28 gennaio 2022): 1517. http://dx.doi.org/10.3390/ijms23031517.
Abstract (sommario):
In response to exercise, the oxidative capacity of mitochondria within skeletal muscle increases through the coordinated expression of mitochondrial proteins in a process termed mitochondrial biogenesis. Controlling the expression of mitochondrial proteins are transcription factors—a group of proteins that regulate messenger RNA transcription from DNA in the nucleus and mitochondria. To fulfil other functions or to limit gene expression, transcription factors are often localised away from DNA to different subcellular compartments and undergo rapid movement or accumulation only when required. Although many transcription factors involved in exercise-induced mitochondrial biogenesis have been identified, numerous conflicting findings and gaps exist within our knowledge of their subcellular movement. This review aims to summarise and provide a critical analysis of the published literature regarding the exercise-induced movement of transcription factors involved in mitochondria biogenesis in skeletal muscle.
12
Iqbal, Sobia, e David A. Hood. "Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts". American Journal of Physiology-Cell Physiology 306, n. 12 (15 giugno 2014): C1176—C1183. http://dx.doi.org/10.1152/ajpcell.00017.2014.
Abstract (sommario):
Mitochondria are dynamic organelles, capable of altering their morphology and function. However, the mechanisms governing these changes have not been fully elucidated, particularly in muscle cells. We demonstrated that oxidative stress with H2O2 resulted in a 41% increase in fragmentation of the mitochondrial reticulum in myoblasts within 3 h of exposure, an effect that was preceded by a reduction in membrane potential. Using live cell imaging, we monitored mitochondrial motility and found that oxidative stress resulted in a 30% reduction in the average velocity of mitochondria. This was accompanied by parallel reductions in both organelle fission and fusion. The attenuation in mitochondrial movement was abolished by the addition of N-acetylcysteine. To investigate whether H2O2-induced fragmentation was mediated by dynamin-related protein 1, we incubated cells with mDivi1, an inhibitor of dynamin-related protein 1 translocation to mitochondria. mDivi1 attenuated oxidative stress-induced mitochondrial fragmentation by 27%. Moreover, we demonstrated that exposure to H2O2 upregulated endoplasmic reticulum-unfolded protein response markers before the initiation of mitophagy signaling and the mitochondrial-unfolded protein response. These findings indicate that oxidative stress is a vital signaling mechanism in the regulation of mitochondrial morphology and motility.
13
Koopman, Werner J. H., Felix Distelmaier, Mark A. Hink, Sjoerd Verkaart, Mietske Wijers, Jack Fransen, Jan A. M. Smeitink e Peter H. G. M. Willems. "Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria". American Journal of Physiology-Cell Physiology 294, n. 5 (maggio 2008): C1124—C1132. http://dx.doi.org/10.1152/ajpcell.00079.2008.
Abstract (sommario):
Mitochondria continuously change shape, position, and matrix configuration for optimal metabolite exchange. It is well established that changes in mitochondrial metabolism influence mitochondrial shape and matrix configuration. We demonstrated previously that inhibition of mitochondrial complex I (CI or NADH:ubiquinone oxidoreductase) by rotenone accelerated matrix protein diffusion and decreased the fraction and velocity of moving mitochondria. In the present study, we investigated the relationship between inherited CI deficiency, mitochondrial shape, mobility, and matrix protein diffusion. To this end, we analyzed fibroblasts of two children that represented opposite extremes in a cohort of 16 patients, with respect to their residual CI activity and mitochondrial shape. Fluorescence correlation spectroscopy (FCS) revealed no relationship between residual CI activity, mitochondrial shape, the fraction of moving mitochondria, their velocity, and the rate of matrix-targeted enhanced yellow fluorescent protein (mitoEYFP) diffusion. However, mitochondrial velocity and matrix protein diffusion in moving mitochondria were two to three times higher in patient cells than in control cells. Nocodazole inhibited mitochondrial movement without altering matrix EYFP diffusion, suggesting that both activities are mutually independent. Unexpectedly, electron microscopy analysis revealed no differences in mitochondrial ultrastructure between control and patient cells. It is discussed that the matrix of a moving mitochondrion in the CI-deficient state becomes less dense, allowing faster metabolite diffusion, and that fibroblasts of CI-deficient patients become more glycolytic, allowing a higher mitochondrial velocity.
14
Zheng, Yanrong, Xiangnan Zhang, Xiaoli Wu, Lei Jiang, Anil Ahsan, Shijia Ma, Ziyu Xiao et al. "Somatic autophagy of axonal mitochondria in ischemic neurons". Journal of Cell Biology 218, n. 6 (12 aprile 2019): 1891–907. http://dx.doi.org/10.1083/jcb.201804101.
Abstract (sommario):
Mitophagy protects against ischemic neuronal injury by eliminating damaged mitochondria, but it is unclear how mitochondria in distal axons are cleared. We find that oxygen and glucose deprivation-reperfusion reduces mitochondrial content in both cell bodies and axons. Axonal mitochondria elimination was not abolished in Atg7fl/fl;nes-Cre neurons, suggesting the absence of direct mitophagy in axons. Instead, axonal mitochondria were enwrapped by autophagosomes in soma and axon-derived mitochondria prioritized for elimination by autophagy. Intriguingly, axonal mitochondria showed prompt loss of anterograde motility but increased retrograde movement upon reperfusion. Anchoring of axonal mitochondria by syntaphilin blocked neuronal mitophagy and aggravated injury. Conversely, induced binding of mitochondria to dynein reinforced retrograde transport and enhanced mitophagy to prevent mitochondrial dysfunction and attenuate neuronal injury. Therefore, we reveal somatic autophagy of axonal mitochondria in ischemic neurons and establish a direct link of retrograde mitochondrial movement with mitophagy. Our findings may provide a new concept for reducing ischemic neuronal injury by correcting mitochondrial motility.
15
Smith, M. G., V. R. Simon, H. O'Sullivan e L. A. Pon. "Organelle-cytoskeletal interactions: actin mutations inhibit meiosis-dependent mitochondrial rearrangement in the budding yeast Saccharomyces cerevisiae." Molecular Biology of the Cell 6, n. 10 (ottobre 1995): 1381–96. http://dx.doi.org/10.1091/mbc.6.10.1381.
Abstract (sommario):
During early stages of meiosis I, yeast mitochondria fuse to form a single continuous thread. Thereafter, portions of the mitochondrial thread are equally distributed to daughter cells. Using time-lapse fluorescence microscopy and a membrane potential sensing dye, mitochondria are resolved as small particles at the cell periphery in pre-meiotic, living yeast. These organelles display low levels of movement. During meiosis I, we observed a threefold increase in mitochondrial motility. Mitochondrial movements were linear, occurred at a maximum velocity of 25 +/- 6.7 nm/s, and resulted in organelle collision and fusion to form elongated tubular structures. Mitochondria do not co-localize with microtubules. Destabilization of microtubules by nocodazole treatment has no significant effect on the rate and extent of thread formation. In contrast, yeast bearing temperature-sensitive mutations in the actin-encoding ACT1 gene (act1-3 and act1-133) exhibit abnormal mitochondrial aggregation, fragmentation, and enlargement as well as loss of mitochondrial motility. In act1-3 cells, mitochondrial defects and actin delocalization occur only at restrictive temperatures. The act1-133 mutation, which perturbs the myosin-binding site of actin without significantly affecting actin cytoskeletal structure in meiotic yeast, results in mitochondrial morphology and motility defects at restrictive and permissive temperatures. These studies support a role for the actin cytoskeleton in the control of mitochondrial position and movements in meiotic yeast.
16
Boldogh, Istvan, Nikola Vojtov, Sharon Karmon e Liza A. Pon. "Interaction between Mitochondria and the Actin Cytoskeleton in Budding Yeast Requires Two Integral Mitochondrial Outer Membrane Proteins, Mmm1p and Mdm10p". Journal of Cell Biology 141, n. 6 (15 giugno 1998): 1371–81. http://dx.doi.org/10.1083/jcb.141.6.1371.
Abstract (sommario):
Transfer of mitochondria to daughter cells during yeast cell division is essential for viable progeny. The actin cytoskeleton is required for this process, potentially as a track to direct mitochondrial movement into the bud. Sedimentation assays reveal two different components required for mitochondria–actin interactions: (1) mitochondrial actin binding protein(s) (mABP), a peripheral mitochondrial outer membrane protein(s) with ATP-sensitive actin binding activity, and (2) a salt-inextractable, presumably integral, membrane protein(s) required for docking of mABP on the organelle. mABP activity is abolished by treatment of mitochondria with high salt. Addition of either the salt-extracted mitochondrial peripheral membrane proteins (SE), or a protein fraction with ATP-sensitive actin-binding activity isolated from SE, to salt-washed mitochondria restores this activity. mABP docking activity is saturable, resistant to high salt, and inhibited by pre-treatment of salt-washed mitochondria with papain. Two integral mitochondrial outer membrane proteins, Mmm1p (Burgess, S.M., M. Delannoy, and R.E. Jensen. 1994. J.Cell Biol. 126:1375–1391) and Mdm10p, (Sogo, L.F., and M.P. Yaffe. 1994. J.Cell Biol. 126:1361– 1373) are required for these actin–mitochondria interactions. Mitochondria isolated from an mmm1-1 temperature-sensitive mutant or from an mdm10 deletion mutant show no mABP activity and no mABP docking activity. Consistent with this, mitochondrial motility in vivo in mmm1-1 and mdm10Δ mutants appears to be actin independent. Depolymerization of F-actin using latrunculin-A results in loss of long-distance, linear movement and a fivefold decrease in the velocity of mitochondrial movement. Mitochondrial motility in mmm1-1 and mdm10Δ mutants is indistinguishable from that in latrunculin-A–treated wild-type cells. We propose that Mmm1p and Mdm10p are required for docking of mABP on the surface of yeast mitochondria and coupling the organelle to the actin cytoskeleton.
17
Liesa, Marc, Manuel Palacín e Antonio Zorzano. "Mitochondrial Dynamics in Mammalian Health and Disease". Physiological Reviews 89, n. 3 (luglio 2009): 799–845. http://dx.doi.org/10.1152/physrev.00030.2008.
Abstract (sommario):
The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes ( MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.
18
Zerihun, Mulate, Surya Sukumaran e Nir Qvit. "The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy". International Journal of Molecular Sciences 24, n. 6 (17 marzo 2023): 5785. http://dx.doi.org/10.3390/ijms24065785.
Abstract (sommario):
Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly vibrant movement and distribution of mitochondria within cells is controlled by the highly coordinated interplay between mitochondrial dynamic processes and fission and fusion events, as well as mitochondrial quality-control processes, mainly mitochondrial autophagy (also known as mitophagy). Fusion connects and unites neighboring depolarized mitochondria to derive a healthy and distinct mitochondrion. In contrast, fission segregates damaged mitochondria from intact and healthy counterparts and is followed by selective clearance of the damaged mitochondria via mitochondrial specific autophagy, i.e., mitophagy. Hence, the mitochondrial processes encompass all coordinated events of fusion, fission, mitophagy, and biogenesis for sustaining mitochondrial homeostasis. Accumulated evidence strongly suggests that mitochondrial impairment has already emerged as a core player in the pathogenesis, progression, and development of various human diseases, including cardiovascular ailments, the leading causes of death globally, which take an estimated 17.9 million lives each year. The crucial factor governing the fission process is the recruitment of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, from the cytosol to the outer mitochondrial membrane in a guanosine triphosphate (GTP)-dependent manner, where it is oligomerized and self-assembles into spiral structures. In this review, we first aim to describe the structural elements, functionality, and regulatory mechanisms of the key mitochondrial fission protein, Drp1, and other mitochondrial fission adaptor proteins, including mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics 49 (Mid49), and mitochondrial dynamics 51 (Mid51). The core area of the review focuses on the recent advances in understanding the role of the Drp1-mediated mitochondrial fission adaptor protein interactome to unravel the missing links of mitochondrial fission events. Lastly, we discuss the promising mitochondria-targeted therapeutic approaches that involve fission, as well as current evidence on Drp1-mediated fission protein interactions and their critical roles in the pathogeneses of cardiovascular diseases (CVDs).
19
Altmann, Katrin, Martina Frank, Daniel Neumann, Stefan Jakobs e Benedikt Westermann. "The class V myosin motor protein, Myo2, plays a major role in mitochondrial motility in Saccharomyces cerevisiae". Journal of Cell Biology 181, n. 1 (7 aprile 2008): 119–30. http://dx.doi.org/10.1083/jcb.200709099.
Abstract (sommario):
The actin cytoskeleton is essential for polarized, bud-directed movement of cellular membranes in Saccharomyces cerevisiae and thus ensures accurate inheritance of organelles during cell division. Also, mitochondrial distribution and inheritance depend on the actin cytoskeleton, though the precise molecular mechanisms are unknown. Here, we establish the class V myosin motor protein, Myo2, as an important mediator of mitochondrial motility in budding yeast. We found that mutants with abnormal expression levels of Myo2 or its associated light chain, Mlc1, exhibit aberrant mitochondrial morphology and loss of mitochondrial DNA. Specific mutations in the globular tail of Myo2 lead to aggregation of mitochondria in the mother cell. Isolated mitochondria lacking functional Myo2 are severely impaired in their capacity to bind to actin filaments in vitro. Time-resolved fluorescence microscopy revealed a block of bud-directed anterograde mitochondrial movement in cargo binding–defective myo2 mutant cells. We conclude that Myo2 plays an important and direct role for mitochondrial motility and inheritance in budding yeast.
20
Sogo, L. F., e M. P. Yaffe. "Regulation of mitochondrial morphology and inheritance by Mdm10p, a protein of the mitochondrial outer membrane." Journal of Cell Biology 126, n. 6 (15 settembre 1994): 1361–73. http://dx.doi.org/10.1083/jcb.126.6.1361.
Abstract (sommario):
Yeast cells with the mdm10 mutation possess giant spherical mitochondria and are defective for mitochondrial inheritance. The giant mitochondria display classical features of mitochondrial ultrastructure, yet they appear incapable of movement or division. Genetic analysis indicated that the mutant phenotypes resulted from a single nuclear mutation, and the isolated MDM10 gene restored wild-type mitochondrial distribution and morphology when introduced into mutant cells. MDM10 encodes a protein of 56.2 kD located in the mitochondrial outer membrane. Depletion of Mdm10p from cells led to a condensation of normally extended, tubular mitochondria into giant spheres, and reexpression of the protein resulted in a rapid restoration of normal mitochondrial morphology. These results demonstrate that Mdm10p can control mitochondrial morphology, and that it plays a role in the inheritance of mitochondria.
21
Boldogh, Istvan R., Sharmilee L. Ramcharan, Hyeong-Cheol Yang e Liza A. Pon. "A Type V Myosin (Myo2p) and a Rab-like G-Protein (Ypt11p) Are Required for Retention of Newly Inherited Mitochondria in Yeast Cells during Cell Division". Molecular Biology of the Cell 15, n. 9 (settembre 2004): 3994–4002. http://dx.doi.org/10.1091/mbc.e04-01-0053.
Abstract (sommario):
Two actin-dependent force generators contribute to mitochondrial inheritance: Arp2/3 complex and the myosin V Myo2p (together with its Rab-like binding partner Ypt11p). We found that deletion of YPT11, reduction of the length of the Myo2p lever arm (myo2-Δ6IQ), or deletion of MYO4 (the other yeast myosin V), had no effect on mitochondrial morphology, colocalization of mitochondria with actin cables, or the velocity of bud-directed mitochondrial movement. In contrast, retention of mitochondria in the bud was compromised in YPT11 and MYO2 mutants. Retention of mitochondria in the bud tip of wild-type cells results in a 60% decrease in mitochondrial movement in buds compared with mother cells. In ypt11Δ mutants, however, the level of mitochondrial motility in buds was similar to that observed in mother cells. Moreover, the myo2-66 mutant, which carries a temperature-sensitive mutation in the Myo2p motor domain, exhibited a 55% decrease in accumulation of mitochondria in the bud tip, and an increase in accumulation of mitochondria at the retention site in the mother cell after shift to restrictive temperatures. Finally, destabilization of actin cables and the resulting delocalization of Myo2p from the bud tip had no significant effect on the accumulation of mitochondria in the bud tip.
22
Wei, Wei, e Gary Ruvkun. "Lysosomal activity regulatesCaenorhabditis elegansmitochondrial dynamics through vitamin B12 metabolism". Proceedings of the National Academy of Sciences 117, n. 33 (31 luglio 2020): 19970–81. http://dx.doi.org/10.1073/pnas.2008021117.
Abstract (sommario):
Mitochondrial fission and fusion are highly regulated by energy demand and physiological conditions to control the production, activity, and movement of these organelles. Mitochondria are arrayed in a periodic pattern inCaenorhabditis elegansmuscle, but this pattern is disrupted by mutations in the mitochondrial fission component dynamin DRP-1. Here we show that the dramatically disorganized mitochondria caused by a mitochondrial fission-defective dynamin mutation is strongly suppressed to a more periodic pattern by a second mutation in lysosomal biogenesis or acidification. Vitamin B12 is normally imported from the bacterial diet via lysosomal degradation of B12-binding proteins and transport of vitamin B12 to the mitochondrion and cytoplasm. We show that the lysosomal dysfunction induced by gene inactivations of lysosomal biogenesis or acidification factors causes vitamin B12 deficiency. Growth of theC. elegansdynamin mutant on anEscherichia colistrain with low vitamin B12 also strongly suppressed the mitochondrial fission defect. Of the twoC. elegansenzymes that require B12, gene inactivation of methionine synthase suppressed the mitochondrial fission defect of a dynamin mutation. We show that lysosomal dysfunction induced mitochondrial biogenesis, which is mediated by vitamin B12 deficiency and methionine restriction. S-adenosylmethionine, the methyl donor of many methylation reactions, including histones, is synthesized from methionine by S-adenosylmethionine synthase; inactivation of thesams-1S-adenosylmethionine synthase also suppresses thedrp-1fission defect, suggesting that vitamin B12 regulates mitochondrial biogenesis and then affects mitochondrial fission via chromatin pathways.
23
ROSS, Meredith F., Aleksandra FILIPOVSKA, Robin A. J. SMITH, Michael J. GAIT e Michael P. MURPHY. "Cell-penetrating peptides do not cross mitochondrial membranes even when conjugated to a lipophilic cation: evidence against direct passage through phospholipid bilayers". Biochemical Journal 383, n. 3 (26 ottobre 2004): 457–68. http://dx.doi.org/10.1042/bj20041095.
Abstract (sommario):
CPPs (cell-penetrating peptides) facilitate the cellular uptake of covalently attached oligonucleotides, proteins and other macromolecules, but the mechanism of their uptake is disputed. Two models are proposed: direct movement through the phospholipid bilayer and endocytic uptake. Mitochondria are a good model system to distinguish between these possibilities, since they have no vesicular transport systems. Furthermore, CPP-mediated delivery of macromolecules to the mitochondrial matrix would be a significant breakthrough in the study of mitochondrial function and dysfunction, and could also lead to new therapies for diseases caused by mitochondrial damage. Therefore we investigated whether two CPPs, penetratin and Tat, could act as mitochondrial delivery vectors. We also determined whether conjugation of the lipophilic cation TPP (triphenylphosphonium) to penetratin or Tat facilitated their uptake into mitochondria, since TPP leads to uptake of attached molecules into mitochondria driven by the membrane potential. Neither penetratin nor Tat, nor their TPP conjugates, are internalized by isolated mitochondria, indicating that these CPPs cannot cross mitochondrial phospholipid bilayers. Tat and TPP–Tat are taken up by cells, but they accumulate in endosomes and do not reach mitochondria. We conclude that CPPs cannot cross mitochondrial phospholipid bilayers, and therefore cannot deliver macromolecules directly to mitochondria. Our findings shed light on the mechanism of uptake of CPPs by cells. The lack of direct movement of CPPs through mitochondrial phospholipid bilayers, along with the observed endosomal accumulation of Tat and TPP–Tat in cells, makes it unlikely that CPPs enter cells by direct membrane passage, and instead favours cellular uptake via an endocytic pathway.
24
Morris, R. L., e P. J. Hollenbeck. "The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth". Journal of Cell Science 104, n. 3 (1 marzo 1993): 917–27. http://dx.doi.org/10.1242/jcs.104.3.917.
Abstract (sommario):
Although small molecules such as ATP diffuse freely in the cytosol, many types of cells nonetheless position their mitochondria in regions of intense ATP consumption. We reasoned that in the highly elongated axonal processes of growing neurons in culture, the active growth cone would form a focus of ATP consumption so distant from the cell body as to require the positioning of mitochondria nearby via regulated axonal transport. To test this hypothesis, we quantified the distribution and transport behavior of mitochondria in live, aerobically respiring chick sympathetic neurons. We found that in the distal region of actively growing axons, the distribution of mitochondria was highly skewed toward the growth cone, with a sevenfold higher density in the region immediately adjacent to the growth cone than in the region 100 microns away. When axonal outgrowth was blocked by substratum-associated barriers or mild cytochalasin E treatment, the gradient of mitochondrial distribution collapsed as mitochondria exited retrogradely from the distal region, becoming uniformly distributed along the axon within one hour. Analysis of individual mitochondrial behaviors revealed that mitochondrial movement everywhere was bidirectional but balanced so that net transport was anterograde in growing axons and retrograde in blocked axons. This reversal in net transport derived from two separate modulations of mitochondrial movement. First, moving mitochondria underwent a transition to a persistently stationary state in the region of active growth cones that was reversed when growth cone activity was halted. Second, the fraction of time that mitochondria spent moving anterogradely was sharply reduced in non-growing axons. Together, these could account for the formation of gradients of mitochondria in growing axons and their dissipation when outgrowth was blocked. This regulated transport behavior was not dependent upon the ability of mitochondria to produce ATP. Our data indicate that mitochondria possess distinct motor activities for both directions of movement and that mitochondrial transport in axons is regulated by both recruitment between stationary and moving states, and direct regulation of the anterograde motor.
25
Tranchant, C., e M. Anheim. "Movement disorders in mitochondrial diseases". Revue Neurologique 172, n. 8-9 (agosto 2016): 524–29. http://dx.doi.org/10.1016/j.neurol.2016.07.003.
26
Flønes, Irene H., e Charalampos Tzoulis. "Movement disorders in mitochondrial disease". Current Opinion in Neurology 31, n. 4 (agosto 2018): 472–83. http://dx.doi.org/10.1097/wco.0000000000000583.
27
Ghaoui, Roula, e Carolyn M. Sue. "Movement disorders in mitochondrial disease". Journal of Neurology 265, n. 5 (6 gennaio 2018): 1230–40. http://dx.doi.org/10.1007/s00415-017-8722-6.
28
Schulz, Jorg B., e M. Flint Beal. "Mitochondrial dysfunction in movement disorders". Current Opinion in Neurology 7, n. 4 (agosto 1994): 333–39. http://dx.doi.org/10.1097/00019052-199408000-00010.
29
Hanna, Michael G., e Kailash P. Bhatia. "Movement disorders and mitochondrial dysfunction". Current Opinion in Neurology 10, n. 4 (agosto 1997): 351–56. http://dx.doi.org/10.1097/00019052-199708000-00012.
30
Li, Yan, Seung Lim, David Hoffman, Pontus Aspenstrom, Howard J. Federoff e David A. Rempe. "HUMMR, a hypoxia- and HIF-1α–inducible protein, alters mitochondrial distribution and transport". Journal of Cell Biology 185, n. 6 (15 giugno 2009): 1065–81. http://dx.doi.org/10.1083/jcb.200811033.
Abstract (sommario):
Mitochondrial transport is critical for maintenance of normal neuronal function. Here, we identify a novel mitochondria protein, hypoxia up-regulated mitochondrial movement regulator (HUMMR), which is expressed in neurons and is markedly induced by hypoxia-inducible factor 1 α (HIF-1α). Interestingly, HUMMR interacts with Miro-1 and Miro-2, mitochondrial proteins that are critical for mediating mitochondrial transport. Interestingly, knockdown of HUMMR or HIF-1 function in neurons exposed to hypoxia markedly reduces mitochondrial content in axons. Because mitochondrial transport and distribution are inextricably linked, the impact of reduced HUMMR function on the direction of mitochondrial transport was also explored. Loss of HUMMR function in hypoxia diminished the percentage of motile mitochondria moving in the anterograde direction and enhanced the percentage moving in the retrograde direction. Thus, HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. These findings have broad implications for maintenance of neuronal viability and function during physiological and pathological states.
31
Qin, Yuan, Wenting Jiang, Anqi Li, Meng Gao, Hanyu Liu, Yufei Gao, Xiangang Tian e Guohua Gong. "The Combination of Paraformaldehyde and Glutaraldehyde Is a Potential Fixative for Mitochondria". Biomolecules 11, n. 5 (10 maggio 2021): 711. http://dx.doi.org/10.3390/biom11050711.
Abstract (sommario):
Mitochondria are highly dynamic organelles, constantly undergoing shape changes, which are controlled by mitochondrial movement, fusion, and fission. Mitochondria play a pivotal role in various cellular processes under physiological and pathological conditions, including metabolism, superoxide generation, calcium homeostasis, and apoptosis. Abnormal mitochondrial morphology and mitochondrial protein expression are always closely related to the health status of cells. Analysis of mitochondrial morphology and mitochondrial protein expression in situ is widely used to reflect the abnormality of cell function in the chemical fixed sample. Paraformaldehyde (PFA), the most commonly used fixative in cellular immunostaining, still has disadvantages, including loss of antigenicity and disruption of morphology during fixation. We tested the effect of ethanol (ETHO), PFA, and glutaraldehyde (GA) fixation on cellular mitochondria. The results showed that 3% PFA and 1.5% GA (PFA-GA) combination reserved mitochondrial morphology better than them alone in situ in cells. Mitochondrial network and protein antigenicity were well maintained, indicated by preserved MitoTracker and mitochondrial immunostaining after PFA-GA fixation. Our results suggest that the PFA-GA combination is a valuable fixative for the study of mitochondria in situ.
32
Raza, Hussain. "HEAVY METAL POLLUTANT-INDUCED CYTOTOXICITY INVOLVES PERTURBATIONS OF MITOCHONDRIAL FUNCTION". Paediatrics & Child Health 23, suppl_1 (18 maggio 2018): e38-e39. http://dx.doi.org/10.1093/pch/pxy054.100.
Abstract (sommario):
Abstract BACKGROUND Environmental pollutants like heavy metals pose a tremendous risk to both animal and human health though the mechanisms underlying their cytotoxic actions at the cellular level remain largely unknown. The freshwater mollusc Lymnaea stagnalis carries hemocynin as its oxygen carrier whereby iron is replaced with copper. As such, this species is highly sensitive to its environmental copper contents and has been used as an important indicator of water quality. Studies have shown that miniscule levels of heavy metals (Pb, Ni, Cu, Co) dissolved in aqueous environments lead to detrimental effects on many of the Lymanea’s vital functions – including respiration and cardiac functions. OBJECTIVES The objective was to determine how heavy metal pulliutants target the cell and its vital functions and if the detirioration of cell motility and viability is a result of the reduced functioning and potential of the cells mitochondria. DESIGN/METHODS We tested the effects of Cu (EC20 as low as 1.8 ug L-1) on isolated blood cells (hemocytes) and neurons from Lymnaea. We sought to determine whether Cu2+ affected cellular viability, motility and neuronal growth cone movements involving cytoskeletal proteins such as actin and tubulin. Cells from the brain were harvested and plated on sigma coated dishes and left to incubate for 3 days to adjust to the environement. They were then stained with mitortracker dyes for mitochondrial potential and movement. The results were captured through live cell imaging and were later analyzed using neurite tracer. We demonstrate the effects of Cu on single mitochondrial movements, structure and function. RESULTS This study provides the first direct evidence that heavy metals such as Cu are indeed cytotoxic and that its detrimental effects on animal health likely involve perturbations of mitochondrial structure and function. Mitochondrial accumulation within the cell started detirioraiting within the first hour of live cell imaging. The mitochondria within the tested cells also started chainging how they cluster within an expanding growth cone. Mitochondrial density decreased substantially and clustered mitohochondira became more fragmeneted which is a positive indication of mitochndrial malfunction. The mitochondrial potential dropped substantially too, indicating that the mitochondria were unable to produce energy like they are suppose to in normal conditions. Finally, this also allowed us to show why heavy metal use in the dentistry profession and other medical professions where heavy metals are used can be linked to cell apoptosis and mitochondrial degradation. CONCLUSION Heavy metals indeed cause malfunction within the cells mitochondria and the reduced functioning disables the cells from fulfilling their associated functions. This was observed through the reduction of breathing, mastication, movement, and neuronal firing of the Lymnaea, which shows a direct realtionship to degraded mitochondria within these cells. Similar results were seen within the hemocytes, which demonstrates that their function of circulating and delivering oxygen was also impaired due to faulty mitochondria.
33
Gao, Junjie, An Qin, Delin Liu, Rui Ruan, Qiyang Wang, Jun Yuan, Tak Sum Cheng et al. "Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network". Science Advances 5, n. 11 (novembre 2019): eaaw7215. http://dx.doi.org/10.1126/sciadv.aaw7215.
Abstract (sommario):
Mitochondrial transfer plays a crucial role in the regulation of tissue homeostasis and resistance to cancer chemotherapy. Osteocytes have interconnecting dendritic networks and are a model to investigate its mechanism. We have demonstrated, in primary murine osteocytes with photoactivatable mitochondria (PhAM)floxed and in MLO-Y4 cells, mitochondrial transfer in the dendritic networks visualized by high-resolution confocal imaging. Normal osteocytes transferred mitochondria to adjacent metabolically stressed osteocytes and restored their metabolic function. The coordinated movement and transfer of mitochondria within the dendritic network rely on contact between the endoplasmic reticulum (ER) and mitochondria. Mitofusin 2 (Mfn2), a GTPase that tethers ER to mitochondria, predominantly mediates the transfer. A decline in Mfn2 expression with age occurs concomitantly with both impaired mitochondrial distribution and transfer in the osteocyte dendritic network. These data show a previously unknown function of ER-mitochondrial contact in mediating mitochondrial transfer and provide a mechanism to explain the homeostasis of osteocytes.
34
Oakley, B. R., e J. E. Rinehart. "Mitochondria and nuclei move by different mechanisms in Aspergillus nidulans." Journal of Cell Biology 101, n. 6 (1 dicembre 1985): 2392–97. http://dx.doi.org/10.1083/jcb.101.6.2392.
Abstract (sommario):
We have examined the effects of the antimicrotubule agent benomyl and several mutations on nuclear and mitochondrial movement in germlings of the filamentous fungus Aspergillus nidulans. While, as previously reported, benomyl inhibited nuclear division and movement, it did not inhibit mitochondrial movement. To test the effects of benomyl more rigorously, we germinated two benomyl super-sensitive, beta-tubulin mutants at a benomyl concentration 50-100 times greater than that required to inhibit colony formation completely. Again nuclear division and movement were inhibited, but mitochondrial movement was not. We also examined conditionally lethal beta-tubulin mutations that disrupt microtubule function under restrictive conditions. Nuclear division and movement were inhibited but, again, mitochondrial movement was not. Finally we examined the effects of five heat-sensitive mutations that inhibit nuclear movement but not nuclear division at restrictive temperatures. These mutations strongly inhibited nuclear movement at a restrictive temperature but did not inhibit mitochondrial movement. These data demonstrate that the mechanisms of nuclear and mitochondrial movement in Aspergillus nidulans are not identical and suggest that mitochondrial movement does not require functional microtubules.
35
Kim, Ji-Yon, So-Youn Woo, Young Bin Hong, Heesun Choi, Jisoo Kim, Hyunjung Choi, Inhee Mook-Jung et al. "HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation". Stem Cells International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/9475981.
Abstract (sommario):
The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.
36
Reichman, N., C. M. Porteous e M. P. Murphy. "Cyclosporin A blocks 6-hydroxydopamine-induced efflux of Ca2+ from mitochondria without inactivating the mitochondrial inner-membrane pore". Biochemical Journal 297, n. 1 (1 gennaio 1994): 151–55. http://dx.doi.org/10.1042/bj2970151.
Abstract (sommario):
Oxidative stress causes Ca(2+)-loaded mitochondria to release Ca2+. The mechanism of this efflux is unclear, but it appears to be associated with the opening of a pore in the mitochondrial inner membrane. Pore opening depolarizes the mitochondria, letting solutes enter the mitochondrial matrix, causing swelling. Cyclosporin A (CsA) prevents opening of this pore. The neurotoxin 6-hydroxydopamine (6HD) autoxidizes, producing free radicals, which cause oxidative stress. In this paper it is shown that 6HD-induced efflux from Ca(2+)-loaded mitochondria was prevented by CsA. The 6HD-induced Ca2+ efflux was not accompanied by mitochondrial swelling, depolarization of the mitochondrial inner membrane or movement of radiolabelled sucrose into the mitochondrial matrix. In agreement with others [Schlegel, Schweizer and Richter (1992) Biochem. J. 285, 65-69], these findings suggest that the mitochondrial pore remained closed during pro-oxidant-induced Ca2+ efflux. However, the implication that CsA blocks pro-oxidant-induced Ca2+ efflux by some mechanism other than inactivating the mitochondrial pore, suggests that the interaction of CsA with mitochondria may be more complex than is currently supposed.
37
Cho, Min Jeong, Yu Jin Kim, Won Dong Yu, You Shin Kim e Jae Ho Lee. "Microtubule Integrity Is Associated with the Functional Activity of Mitochondria in HEK293". Cells 10, n. 12 (20 dicembre 2021): 3600. http://dx.doi.org/10.3390/cells10123600.
Abstract (sommario):
Mitochondria move along the microtubule network and produce bioenergy in the cell. However, there is no report of a relationship between bioenergetic activity of mitochondria and microtubule stability in mammalian cells. This study aimed to investigate this relationship. We treated HEK293 cells with microtubule stabilizers (Taxol and Epothilone D) or a microtubule disturber (vinorelbine), and performed live-cell imaging to determine whether mitochondrial morphology and bioenergetic activity depend on the microtubule status. Treatment with microtubule stabilizers enhanced the staining intensity of microtubules, significantly increased ATP production and the spare respiratory capacity, dramatically increased mitochondrial fusion, and promoted dynamic movement of mitochondria. By contrast, bioenergetic activity of mitochondria was significantly decreased in cells treated with the microtubule disturber. Our data suggest that microtubule stability promotes mitochondrial functional activity. In conclusion, a microtubule stabilizer can possibly recover mitochondrial functional activity in cells with unstable microtubules.
38
Yang, Fan, Yanbin Zhang, Sheng Liu, Jiheng Xiao, Yuxin He, Zengwu Shao, Yuhui Zhang, Xianyi Cai e Liming Xiong. "Tunneling Nanotube-Mediated Mitochondrial Transfer Rescues Nucleus Pulposus Cells from Mitochondrial Dysfunction and Apoptosis". Oxidative Medicine and Cellular Longevity 2022 (4 marzo 2022): 1–16. http://dx.doi.org/10.1155/2022/3613319.
Abstract (sommario):
Stem cell-based therapy has been indicated to be beneficial for intervertebral disc regeneration. However, the underlying mechanisms have not been fully identified. The present study showed that bone marrow mesenchymal stem cells (BMSCs) donated mitochondria to adjacent nucleus pulposus cells (NPCs) in a coculture system. The mode of mitochondrial transfer between these cells was intercellular tunneling nanotube (TNT), which acted as a transportation expressway for mitochondria. NPCs acquired additional mitochondria from BMSCs in a concentration-dependent manner after rotenone-induced mitochondrial dysfunction in NPCs. Further research demonstrated that TNT-mediated mitochondrial transfer rescued NPCs from mitochondrial dysfunction and apoptosis, which was indicated by the recovery of the mitochondrial respiratory chain, the increase in mitochondrial membrane potential, and the decreases in reactive oxygen species (ROS) levels and apoptosis rates. Furthermore, Miro1, a critical protein that regulates mitochondrial movement, was knocked down in BMSCs and significantly reduced mitochondrial transfer from BMSCs to NPCs. These results suggested that Miro1 depletion inhibited the rescue of NPCs with mitochondrial dysfunction. Taken together, our data shed light on a novel mechanism by which BMSCs rescue impaired NPCs, providing a concrete foundation to study the critical role of intercellular interactions in disc regeneration.
39
Dayanidhi, Sudarshan. "SKELETAL MUSCLE MITOCHONDRIAL PHYSIOLOGY IN CHILDREN WITH CEREBRAL PALSY: CONSIDERATIONS FOR HEALTHY AGING". Innovation in Aging 6, Supplement_1 (1 novembre 2022): 129. http://dx.doi.org/10.1093/geroni/igac059.516.
Abstract (sommario):
Abstract During healthy aging, there is an overall decline in mitochondrial activity and abundance, increase in mitochondrial DNA mutations, increase in oxidative stress, and reduction in overall muscular capacity. Individuals with cerebral palsy (CP) have significantly increased energetics of movement, reduced endurance capacity, and increased perceived effort. We will cover the results of recent work in muscles in ambulatory children with CP that show a marked reduction in mitochondrial function. Muscles show that mitochondrial protein content and DNA copy number are lower, suggesting a reduction in mitochondrial abundance, along with a reduction in markers for mitochondrial biogenesis. Gene expression networks are reduced for glycolytic and mitochondrial pathways and share similarities with gene networks with aging and chronic inactivity. Given the importance of mitochondria for energy production and changes with aging, ongoing efforts are needed to assess changes in mitochondria across the lifespan in people with CP.
40
Cai, Qian, Claudia Gerwin e Zu-Hang Sheng. "Syntabulin-mediated anterograde transport of mitochondria along neuronal processes". Journal of Cell Biology 170, n. 6 (12 settembre 2005): 959–69. http://dx.doi.org/10.1083/jcb.200506042.
Abstract (sommario):
In neurons, proper distribution of mitochondria in axons and at synapses is critical for neurotransmission, synaptic plasticity, and axonal outgrowth. However, mechanisms underlying mitochondrial trafficking throughout the long neuronal processes have remained elusive. Here, we report that syntabulin plays a critical role in mitochondrial trafficking in neurons. Syntabulin is a peripheral membrane-associated protein that targets to mitochondria through its carboxyl-terminal tail. Using real-time imaging in living cultured neurons, we demonstrate that a significant fraction of syntabulin colocalizes and co-migrates with mitochondria along neuronal processes. Knockdown of syntabulin expression with targeted small interfering RNA or interference with the syntabulin–kinesin-1 heavy chain interaction reduces mitochondrial density within axonal processes by impairing anterograde movement of mitochondria. These findings collectively suggest that syntabulin acts as a linker molecule that is capable of attaching mitochondrial organelles to the microtubule-based motor kinesin-1, and in turn, contributes to anterograde trafficking of mitochondria to neuronal processes.
41
Logan, David C. "Mitochondrial fusion, division and positioning in plants". Biochemical Society Transactions 38, n. 3 (24 maggio 2010): 789–95. http://dx.doi.org/10.1042/bst0380789.
Abstract (sommario):
Mitochondria are involved in many fundamental processes underpinning plant growth, development and death. Owing to their multiple roles, as the sites of the tricarboxylic acid cycle and oxidative phosphorylation, as harbourers of their own genomes and as sensors of cell redox status, amongst others, mitochondria are in a unique position to act as sentinels of cell physiology. The plant chondriome is typically organized as a population of physically discrete organelles, but visualization of mitochondria in living tissues has shown that the mitochondrial population is highly interactive. Mitochondria are highly motile and movement on the cytoskeleton ensures that the physically discrete organelles come into contact with one another, which allows transient fusion, followed by division of the mitochondrial membranes. This article serves to review our current knowledge of mitochondrial fusion and division, and link this to recent discoveries regarding a putative mitochondrial ‘health-check’ and repair process, whereby non-repairable dysfunctional mitochondria can be removed from the chondriome. It is proposed that the unequal distribution of the multipartite plant mitochondrial genome between discrete organelles provides the driver for transient mitochondrial fusion that, in turn, is dependent on mitochondrial motility, and that both fusion and motility are necessary to maintain a healthy functional chondriome.
42
Huertas, Jesus R., Rafael A. Casuso, Pablo Hernansanz Agustín e Sara Cogliati. "Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm". Oxidative Medicine and Cellular Longevity 2019 (19 giugno 2019): 1–18. http://dx.doi.org/10.1155/2019/7058350.
Abstract (sommario):
Skeletal muscles require the proper production and distribution of energy to sustain their work. To ensure this requirement is met, mitochondria form large networks within skeletal muscle cells, and during exercise, they can enhance their functions. In the present review, we discuss recent findings on exercise-induced mitochondrial adaptations. We emphasize the importance of mitochondrial biogenesis, morphological changes, and increases in respiratory supercomplex formation as mechanisms triggered by exercise that may increase the function of skeletal muscles. Finally, we highlight the possible effects of nutraceutical compounds on mitochondrial performance during exercise and outline the use of exercise as a therapeutic tool in noncommunicable disease prevention. The resulting picture shows that the modulation of mitochondrial activity by exercise is not only fundamental for physical performance but also a key point for whole-organism well-being.
43
Chiron, Stéphane, Alyona Bobkova, Haowen Zhou e Michael P. Yaffe. "CLASP regulates mitochondrial distribution in Schizosaccharomyces pombe". Journal of Cell Biology 182, n. 1 (7 luglio 2008): 41–49. http://dx.doi.org/10.1083/jcb.200712147.
Abstract (sommario):
Movement of mitochondria in Schizosaccharomyces pombe depends on their association with the dynamic, or plus ends, of microtubules, yet the molecular basis for this interaction is poorly understood. We identified mmd4 in a screen of temperature-sensitive S. pombe strains for aberrant mitochondrial morphology and distribution. Cells with the mmd4 mutation display mitochondrial aggregation near the cell ends at elevated temperatures, a phenotype similar to mitochondrial defects observed in wild-type cells after microtubule depolymerization. However, microtubule morphology and function appear normal in the mmd4 mutant. The mmd4 lesion maps to peg1+, which encodes a microtubule-associated protein with homology to cytoplasmic linker protein–associated proteins (mammalian microtubule plus end–binding proteins). Peg1p localizes to the plus end of microtubules and to mitochondria and is recovered with mitochondria during subcellular fractionation. This mitochondrial-associated fraction of Peg1p displays properties of a peripherally associated protein. Peg1p is the first identified microtubule plus end–binding protein required for mitochondrial distribution and likely functions as a molecular link between mitochondria and microtubules.
44
Schwindling, Christian, Ariel Quintana, Anna Sylvia Wenning, Ute Becherer, Jens Rettig, Eva C. Schwarz e Markus Hoth. "T-cell activation requires mitochondrial translocation towards the immunological synapse (87.32)". Journal of Immunology 178, n. 1_Supplement (1 aprile 2007): S134. http://dx.doi.org/10.4049/jimmunol.178.supp.87.32.
Abstract (sommario):
Abstract Activation of the adaptive immune response requires the interaction between antigen-presenting cells and T-cells. This cell-cell interaction, called the immunological synapse (IS), facilitates the activation of several T-cell receptor (TCR)-mediated signalling cascades including a rise in the cytosolic Ca2+ concentration ([Ca2+]i) through the activation of CRAC/ORAI1 channels. These channels are opened after depletion of intracellular Ca2+ stores and inactivated by the inflowing Ca2+ itself. We show by epifluorescence, 2-photon and total internal reflection microscopy, that a large fraction of mitochondria was moved to the immediate vicinity of the IS, a process highly dependent on the actin cytoskeleton. Mitochondrial movement to the IS was required to sustain the CRAC/ORAI1-mediated Ca2+ influx. Disruption of the actin cytoskeleton prevented mitochondrial movement and subsequent [Ca2+]i rises. The increased [Ca2+]i signals following interaction of the IS with mitochondria correlated with an enhanced T-cell proliferation. Our results show that actin cytoskeleton-mediated movement of mitochondria into the vicinity of the IS is required to sustain Ca2+ influx and permit efficient T-cell activation. This project was funded by the Deutsche Forschungsgemeinschaft (SFB 530 and GRK 845) and a grant from the Saarland University (HOMFOR).
45
Lee, Jae Ho, Yu Jin Kim, Min Jung Cho, Yun Dong Koo e JuYi Chang. "#124 : Microtubule Stability is Associated with the Functional Activity of Mitochondria for the Mouse Preimplantation Embryo Development". Fertility & Reproduction 05, n. 04 (dicembre 2023): 317. http://dx.doi.org/10.1142/s2661318223741292.
Abstract (sommario):
Background and Aims: Mitochondria have a pivotal role in the quality of embryos and good development to a healthy embryo pregnancy. Also, mitochondrial dysfunction increases during the aging of the embryos. But there is still a debate about the main cause of mitochondrial dysfunction in the aged embryos. We investigate that effect of microtubule stabilizer (MTS) as Taxol, EpD and microtubule disturber (MTD) as VNB in the preimplantation embryo of the mouse. Method: We performed preimplantation embryo culture with MTS and MTD. Then we assess development ratio and mitochondria functional activity between control and MTS and MTD. We performed comparable analysis of mitochondrial motility between MTS treated and MTD treated embryos by confocal live imaging. Results: In the MTS treated embryos, well-developed embryos with microtubules formation were present in the ooplasm. However, in the MTD treated embryos group, less development and poor microtubule polymer formation was observed in the ooplasm. Microtubules was also demonstrated by depolymerization and the clustering form in the ooplasm of MTD treated embryos. The high dynamic movement of the cytoskeleton with a mitochondrion compared to the MTD treated embryos. Conclusion: Our data suggest that the new function of MTS as Taxol, EpD shows promoting competence of embryo development with enhanced activity of a mitochondrial function. Therefore, MTS is useful as a supplement in vitro culture media of embryos.
46
Kumari, Ratan, Nikhila Shekhar, Sakshi Tyagi e Ajit Kumar Thakur. "Mitochondrial dysfunctions and neurodegenerative diseases: a mini-review". Journal of Analytical & Pharmaceutical Research 10, n. 4 (16 agosto 2021): 147–49. http://dx.doi.org/10.15406/japlr.2021.10.00378.
Abstract (sommario):
Mitochondrial dysfunction is estimated to be the primary reason involved in different types of neurodegenerative disorders as mitochondria is suggested to be important in the production of reactive oxygen species. Recently, several evidences have emerged out for impaired mitochondrial structures and functions viz. shape, size, fission-fusion, distribution, movement etc. in neurodegenerative diseases especially with Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Therefore, apart from looking neurodegenerative diseases on the whole, a detailed understanding of the functioning of mitochondria and their role in degeneration would pave new options for the therapy of age-related neurodegenerative diseases.
47
Buneeva, Olga, Valerii Fedchenko, Arthur Kopylov e Alexei Medvedev. "Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA". Biomedicines 8, n. 12 (10 dicembre 2020): 591. http://dx.doi.org/10.3390/biomedicines8120591.
Abstract (sommario):
Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.
48
Maddison, Daniel C., Francesca Mattedi, Alessio Vagnoni e Gaynor Ann Smith. "Analysis of Mitochondrial Dynamics in AdultDrosophilaAxons". Cold Spring Harbor Protocols 2023, n. 2 (30 settembre 2022): pdb.top107819. http://dx.doi.org/10.1101/pdb.top107819.
Abstract (sommario):
Neuronal survival depends on the generation of ATP from an ever-changing mitochondrial network. This requires a fine balance between the constant degradation of damaged mitochondria, biogenesis of new mitochondria, movement along microtubules, dynamic processes, and adequate functional capacity to meet firing demands. The distribution of mitochondria needs to be tightly controlled throughout the entire neuron, including its projections. Axons in particular can be enormous structures compared to the size of the cell soma, and how mitochondria are maintained in these compartments is poorly defined. Mitochondrial dysfunction in neurons is associated with aging and neurodegenerative diseases, with the axon being preferentially vulnerable to destruction.Drosophilaoffer a unique way to study these organelles in fully differentiated adult neurons in vivo. Here, we briefly review the regulation of neuronal mitochondria in health, aging, and disease and introduce two methodological approaches to study mitochondrial dynamics and transport in axons using theDrosophilawing system.
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Hoffmann, Anneliese, Sandro Käser, Martin Jakob, Simona Amodeo, Camille Peitsch, Jiří Týč, Sue Vaughan, Benoît Zuber, André Schneider e Torsten Ochsenreiter. "Molecular model of the mitochondrial genome segregation machinery in Trypanosoma brucei". Proceedings of the National Academy of Sciences 115, n. 8 (6 febbraio 2018): E1809—E1818. http://dx.doi.org/10.1073/pnas.1716582115.
Abstract (sommario):
In almost all eukaryotes, mitochondria maintain their own genome. Despite the discovery more than 50 y ago, still very little is known about how the genome is correctly segregated during cell division. The protozoan parasite Trypanosoma brucei contains a single mitochondrion with a singular genome, the kinetoplast DNA (kDNA). Electron microscopy studies revealed the tripartite attachment complex (TAC) to physically connect the kDNA to the basal body of the flagellum and to ensure correct segregation of the mitochondrial genome via the basal bodies movement, during the cell cycle. Using superresolution microscopy, we precisely localize each of the currently known TAC components. We demonstrate that the TAC is assembled in a hierarchical order from the base of the flagellum toward the mitochondrial genome and that the assembly is not dependent on the kDNA itself. Based on the biochemical analysis, the TAC consists of several nonoverlapping subcomplexes, suggesting an overall size of the TAC exceeding 2.8 mDa. We furthermore demonstrate that the TAC is required for correct mitochondrial organelle positioning but not for organelle biogenesis or segregation.
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Boldogh, Istvan R., Dan W. Nowakowski, Hyeong-Cheol Yang, Haesung Chung, Sharon Karmon, Patrina Royes e Liza A. Pon. "A Protein Complex Containing Mdm10p, Mdm12p, and Mmm1p Links Mitochondrial Membranes and DNA to the Cytoskeleton-based Segregation Machinery". Molecular Biology of the Cell 14, n. 11 (novembre 2003): 4618–27. http://dx.doi.org/10.1091/mbc.e03-04-0225.
Abstract (sommario):
Previous studies indicate that two proteins, Mmm1p and Mdm10p, are required to link mitochondria to the actin cytoskeleton of yeast and for actin-based control of mitochondrial movement, inheritance and morphology. Both proteins are integral mitochondrial outer membrane proteins. Mmm1p localizes to punctate structures in close proximity to mitochondrial DNA (mtDNA) nucleoids. We found that Mmm1p and Mdm10p exist in a complex with Mdm12p, another integral mitochondrial outer membrane protein required for mitochondrial morphology and inheritance. This interpretation is based on observations that 1) Mdm10p and Mdm12p showed the same localization as Mmm1p; 2) Mdm12p, like Mdm10p and Mmm1p, was required for mitochondrial motility; and 3) all three proteins coimmunoprecipitated with each other. Moreover, Mdm10p localized to mitochondria in the absence of the other subunits. In contrast, deletion of MMM1 resulted in mislocalization of Mdm12p, and deletion of MDM12 caused mislocalization of Mmm1p. Finally, we observed a reciprocal relationship between the Mdm10p/Mdm12p/Mmm1p complex and mtDNA. Deletion of any one of the subunits resulted in loss of mtDNA or defects in mtDNA nucleoid maintenance. Conversely, deletion of mtDNA affected mitochondrial motility: mitochondria in cells without mtDNA move 2–3 times faster than mitochondria in cells with mtDNA. These observations support a model in which the Mdm10p/Mdm12p/Mmm1p complex links the minimum heritable unit of mitochondria (mtDNA and mitochondrial outer and inner membranes) to the cytoskeletal system that drives transfer of that unit from mother to daughter cells.