scholarly journals Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 222 ◽  
Author(s):  
Andrey V. Kuznetsov ◽  
Sabzali Javadov ◽  
Michael Grimm ◽  
Raimund Margreiter ◽  
Michael J. Ausserlechner ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Fundamental Problem ◽  
Anion Channel ◽  
Cardiac Cells ◽  
Cytoskeletal Proteins ◽  
Voltage Dependent Anion Channel ◽  
Atp Production ◽  
Regular Arrangement ◽  
Cell Energy

Elucidation of the mitochondrial regulatory mechanisms for the understanding of muscle bioenergetics and the role of mitochondria is a fundamental problem in cellular physiology and pathophysiology. The cytoskeleton (microtubules, intermediate filaments, microfilaments) plays a central role in the maintenance of mitochondrial shape, location, and motility. In addition, numerous interactions between cytoskeletal proteins and mitochondria can actively participate in the regulation of mitochondrial respiration and oxidative phosphorylation. In cardiac and skeletal muscles, mitochondrial positions are tightly fixed, providing their regular arrangement and numerous interactions with other cellular structures such as sarcoplasmic reticulum and cytoskeleton. This can involve association of cytoskeletal proteins with voltage-dependent anion channel (VDAC), thereby, governing the permeability of the outer mitochondrial membrane (OMM) to metabolites, and regulating cell energy metabolism. Cardiomyocytes and myocardial fibers demonstrate regular arrangement of tubulin beta-II isoform entirely co-localized with mitochondria, in contrast to other isoforms of tubulin. This observation suggests the participation of tubulin beta-II in the regulation of OMM permeability through interaction with VDAC. The OMM permeability is also regulated by the specific isoform of cytolinker protein plectin. This review summarizes and discusses previous studies on the role of cytoskeletal proteins in the regulation of energy metabolism and mitochondrial function, adenosine triphosphate (ATP) production, and energy transfer.

scholarly journals On the role of tubulin, plectin, desmin, and vimentin in the regulation of mitochondrial energy fluxes in muscle cells

2019 ◽  
Vol 316 (5) ◽  
pp. C657-C667 ◽  
Author(s):  
Kati Mado ◽  
Vladimir Chekulayev ◽  
Igor Shevchuk ◽  
Marju Puurand ◽  
Kersti Tepp ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Adenine Nucleotides ◽  
Anion Channel ◽  
Muscle Cells ◽  
Eukaryotic Cell ◽  
Cytoskeletal Proteins ◽  
Energy Fluxes ◽  
Voltage Dependent Anion Channel ◽  
And Function

Mitochondria perform a central role in life and death of the eukaryotic cell. They are major players in the generation of macroergic compounds and function as integrated signaling pathways, including the regulation of Ca2+ signals and apoptosis. A growing amount of evidence is demonstrating that mitochondria of muscle cells use cytoskeletal proteins (both microtubules and intermediate filaments) not only for their movement and proper cellular positioning, but also to maintain their biogenesis, morphology, function, and regulation of energy fluxes through the outer mitochondrial membrane (MOM). Here we consider the known literature data concerning the role of tubulin, plectin, desmin and vimentin in bioenergetic function of mitochondria in striated muscle cells, as well as in controlling the permeability of MOM for adenine nucleotides (ADNs). This is of great interest since dysfunctionality of these cytoskeletal proteins has been shown to result in severe myopathy associated with pronounced mitochondrial dysfunction. Further efforts are needed to uncover the pathways by which the cytoskeleton supports the functional capacity of mitochondria and transport of ADN(s) across the MOM (through voltage-dependent anion channel).

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

scholarly journals The Role of Red Cell Energy Metabolism in the Generation of Irreversibly Sickled Cells In Vitro

Blood ◽  
1973 ◽  
Vol 42 (6) ◽  
pp. 835-842 ◽  
Author(s):  
Michael Jensen ◽  
Stephen B. Shohet ◽  
David G. Nathan
Keyword(s):  
Energy Metabolism ◽  
Calcium Metabolism ◽  
Red Cells ◽  
Red Cell ◽  
Hemoglobin S ◽  
Cell Energy ◽  
Incubation Buffer ◽  
Membrane Defect

Abstract An acquired membrane defect is believed to be responsible for the maintenance of the sickled shape in oxygenated irreversibly sickled cells (ISC), because the hemoglobin S in these cells is not in the aggregated, "sickled" state. In the present study, it is demonstrated that the acquisition of the membrane defect in vitro depends on cellular metabolism. Only if cellular ATP is almost completely depleted while the cells are sickled, do they become unable to resume the biconcave disk shape upon reoxygenation. If calcium is omitted from the incubation buffer, ISCs are not generated despite metabolic depletion. This suggests an action of ATP mediated through calcium metabolism similar to that which prevents membrane stiffening in normal red cells. No ISCs were produced by repeated sickling and unsickling. Thus, a membrane alteration occurring as a consequence of metabolic depletion seems to be a more important factor in the generation of ISC than sickling-unsickling induced fragmentation.

scholarly journals Dynamics of enhanced mitochondrial respiration in female compared with male rat cerebral arteries

2015 ◽  
Vol 309 (9) ◽  
pp. H1490-H1500 ◽  
Author(s):  
Ibolya Rutkai ◽  
Somhrita Dutta ◽  
Prasad V. Katakam ◽  
David W. Busija
Keyword(s):  
Mitochondrial Respiration ◽  
Ex Vivo ◽  
Cerebral Arteries ◽  
Anion Channel ◽  
Basal Respiration ◽  
Male Rat ◽  
Sprague Dawley ◽  
Voltage Dependent Anion Channel ◽  
Male And Female ◽  
Atp Production

Mitochondrial respiration has never been directly examined in intact cerebral arteries. We tested the hypothesis that mitochondrial energetics of large cerebral arteries ex vivo are sex dependent. The Seahorse XFe24 analyzer was used to examine mitochondrial respiration in isolated cerebral arteries from adult male and female Sprague-Dawley rats. We examined the role of nitric oxide (NO) on mitochondrial respiration under basal conditions, using Nω-nitro-l-arginine methyl ester, and following pharmacological challenge using diazoxide (DZ), and also determined levels of mitochondrial and nonmitochondrial proteins using Western blot, and vascular diameter responses to DZ. The components of mitochondrial respiration including basal respiration, ATP production, proton leak, maximal respiration, and spare respiratory capacity were elevated in females compared with males, but increased in both male and female arteries in the presence of the NOS inhibitor. Although acute DZ treatment had little effect on mitochondrial respiration of male arteries, it decreased the respiration in female arteries. Levels of mitochondrial proteins in Complexes I–V and the voltage-dependent anion channel protein were elevated in female compared with male cerebral arteries. The DZ-induced vasodilation was greater in females than in males. Our findings show that substantial sex differences in mitochondrial respiratory dynamics exist in large cerebral arteries and may provide the mechanistic basis for observations that the female cerebral vasculature is more adaptable after injury.

scholarly journals AB0052 ROLE OF TRAINED IMMUNITY AND IMMUNOMETABOLISM IN THE PATHOGENESIS OF ERDHEIM-CHESTER DISEASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1328.2-1328
Author(s):  
R. Biavasco ◽  
R. Molteni ◽  
D. Stefanoni ◽  
M. Ferrarini ◽  
E. Ferrero ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Inflammatory Cytokines ◽  
Mapk Pathway ◽  
Inflammatory Activation ◽  
Cell Energy ◽  
Erdheim Chester ◽  
Chester Disease ◽  
Pro Inflammatory Cytokines ◽  
Cell Energy Metabolism

Background:Erdheim-Chester disease (ECD) is a chronic inflammatory disease characterized by infiltration of bone and other tissues by foamy macrophages. These cells exhibit activating mutations along the MAPK pathway, most commonly BRAFV600E, and increased production of pro-inflammatory cytokines. Although this dual neoplastic-inflammatory nature of ECD has long fascinated scientists, the mechanistic link between these two features remains elusive. We hypothesized that Trained Immunity (TI), a pro-inflammatory cell program physiologically elicited in monocytes/macrophages upon activation of the MAPK pathway, might represent the missing link between oncogenic transformation and pro-inflammatory activation in ECD.Objectives:In this study, we aimed at determining the role of TI in the pathogenesis of ECD, and to evaluate the therapeutic potential of targeting this mechanism for the treatment of inflammation.Methods:We developed innovative models to study ECD pathogenesisin vitro(based on lentiviral transduction and ectopic expression of BRAFV600E in primary human monocytes), as well asex vivo(3D culture of ECD tissue biopsies in bioreactor). Functional and mechanistic features of TI, including typical changes in cell energy metabolism and epigenetics, were investigated by assessing I) cytokine and lactate production; II) mitochondrial respiration with Seahorse flux analyzer; III) glucose, glutamine and cholesterol metabolism with unbiased and targeted metabolomics analyses; IV) epigenetic changes with ChIP PCR; V) transcriptome changes with RNA sequencing.Results:Activation of the MAPK pathway induced by BRAFV600E in macrophages induces changes in the epigenetic and gene expression landscape, cell energy metabolism, and cytokine production characteristic of TI. In particular, changes in cell energy metabolism of macrophages are characterized by increased glycolysis, glutamine metabolism, and cholesterol synthesis. This metabolic rewiring is needed to sustain rampant, constitutive production of pro-inflammatory cytokines.Conclusion:A role emerges for TI in the pathogenesis and pro-inflammatory activation of ECD. However, maladaptive activation of this mechanism is likely common to the pathogenesis of other inflammatory and rheumatologic diseases. Since drugs targeting TI programs are already entering the clinical arena, the identification of this mechanism in the pathogenesis of inflammatory and rheumatologic conditions may promptly translate into novel, effective treatment options for affected patients.Disclosure of Interests:Riccardo Biavasco Employee of: Bluebird, Raffaella Molteni: None declared, Davide Stefanoni: None declared, Marina Ferrarini: None declared, Elisabetta Ferrero: None declared, Simone Cenci: None declared, Simone Cardaci: None declared, Alessandra Boletta: None declared, Laura Cassina: None declared, Gianfranco Di Stefano: None declared, Jorge Dominguez Andres: None declared, Claudio Doglioni: None declared, Travis Nemkov: None declared, Ivan Merelli: None declared, Angelo D’Alessandro: None declared, Eugenio Montini: None declared, Mihai Netea: None declared, Lorenzo Dagna: None declared, Giulio Cavalli Consultant of: SOBI, Pfizer, Sanofi, Novartis, Paid instructor for: SOBI, Novartis, Speakers bureau: SOBI, Novartis

scholarly journals The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1737
Author(s):  
Joyce T. Varughese ◽  
Susan K. Buchanan ◽  
Ashley S. Pitt
Keyword(s):  
Physiological Role ◽  
Anion Channel ◽  
Calcium Flux ◽  
Voltage Dependent Anion Channel ◽  
X Ray Crystallography ◽  
Mitochondrial Regulation ◽  
Interaction Partners ◽  
Voltage Dependent ◽  
Conductance States

The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson’s disease (PD), Friedreich’s ataxia (FA), lupus, and cancer. To fully address the molecular role of VDAC in disease pathology, major questions must be answered on the structural conformers of VDAC. For example, further information is needed on the structure of the closed state, how binding partners or membrane potential could lead to the open/closed states, the function and mobility of the N-terminal α-helical domain of VDAC, and the physiological role of VDAC oligomers. This review covers our current understanding of the various states of VDAC, VDAC interaction partners, and the roles they play in mitochondrial regulation pertaining to human diseases.

scholarly journals Role of the O-linked β-N -acetylglucosamine in the Cardioprotection Induced by Isoflurane

2011 ◽  
Vol 115 (5) ◽  
pp. 955-962 ◽  
Author(s):  
Kayo Hirose ◽  
Yasuo M. Tsutsumi ◽  
Rie Tsutsumi ◽  
Masayuki Shono ◽  
Erika Katayama ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Anion Channel ◽  
Cardiac Protection ◽  
Voltage Dependent Anion Channel ◽  
Mptp Opening ◽  
Voltage Dependent

Background Cardiac protection by volatile anesthetic-induced preconditioning and ischemic preconditioning have similar signaling pathways. Recently, it was reported that augmentation of protein modified with O-linked β-N-acetylglucosamine (O-GlcNAc) contributes to cardiac protection. This study investigated the role of O-GlcNAc in cardiac protection induced by anesthetic-induced preconditioning. Methods O-GlcNAc-modified proteins were visualized by immunoblotting. Tolerance against ischemia or reperfusion was tested in vivo (n = 8) and in vitro (n = 6). The opening of the mitochondrial permeability transition pore (mPTP) upon oxidative stress was examined in myocytes treated with calcein AM (n = 5). Coimmunoprecipitation and enzymatic labeling were performed to detect the mitochondrial protein responsible for the mPTP opening. Results Isoflurane treatment and the consequent augmentation of O-GlcNAc concentrations reduced the infarct size (26 ± 5% [mean ± SD], P < 0.001) compared with the control. The protective effect of O-GlcNAc was eliminated in the group pretreated with the O-GlcNAc transferase inhibitor alloxan (39 ± 5%, P < 0.001). Myocyte survival also showed the same result in vitro. Formation of the mPTP was abrogated in the isoflurane-treated cells (86 ± 4%, P < 0.001) compared with the control and alloxan-plus-isoflurane-treated cells (57 ± 7%, P < 0.001). Coimmunoprecipitation and enzymatic labeling studies revealed that the O-GlcNAc-modified, voltage-dependent anion channel restained the mPTP opening. Conclusions Isoflurane induced O-GlcNAc modification of mitochondrial voltage-dependent anion channel. This modification inhibited the opening of the mPTP and conferred resistance to ischemia-reperfusion stress.

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