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Crosstalk Between Mitochondria and Cytoskeleton in Cardiac Cells

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Crosstalk Between Mitochondria and Cytoskeleton in Cardiac Cells cells Review Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells Andrey V. Kuznetsov 1,2,*, Sabzali Javadov 3 , Michael Grimm 1, Raimund Margreiter 4, Michael J. Ausserlechner 2 and Judith Hagenbuchner 5,* 1 Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria; [email protected] 2 Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 3 Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936-5067, USA; [email protected] 4 Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 5 Department of Paediatrics II, Medical University of Innsbruck, 6020 Innsbruck, Austria * Correspondence: [email protected] (A.V.K.); [email protected] (J.H.); Tel.: +43-512-504-27815 (A.V.K.); +43-512-504-81578 (J.H.) Received: 3 December 2019; Accepted: 13 January 2020; Published: 16 January 2020 Abstract: 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. Keywords: heart; cytoskeletal proteins; mitochondria; energy metabolism; mitochondrial interactions; plectin; tubulin beta; signaling 1. Introduction Cells are highly organized units with multifaceted functional and structural interactions between various subcellular systems. A large number of studies provides strong evidence that elucidating individual organelles alone is not sufficient, and only systemic approaches must be applied for understanding intracellular signaling pathways and crosstalk between subcellular organelles. This may involve a “systems biology” approach and combinations of several most modern technologies such as genetic manipulations, live cell imaging, mathematical modelling, etc. In high oxygen consuming Cells 2020, 9, 222; doi:10.3390/cells9010222 www.mdpi.com/journal/cells Cells 2020, 9, x 2 of 23 Cells 2020, 9, 222 2 of 24 organelles. This may involve a “systems biology” approach and combinations of several most modern technologies such as genetic manipulations, live cell imaging, mathematical modelling, etc. organsIn high like oxygen the heart, consuming energy supply organs (ATP) like the is providedheart, energy by mitochondria supply (ATP) in is the provided reactions by of mitochondria oxidative phosphorylationin the reactions (OXPHOS). of oxidative Notably, phosphorylation mitochondria (OXP activelyHOS). interact Notably, with mitochondria other subcellular actively organelles interact andwith systems other likesubcellular cytoskeleton organelles and sarcoplasmic and systems reticulumlike cytoskeleton (SR) [1 –and12]. sarcoplasmic Many cytoskeletal reticulum elements (SR) [1– play12]. a vitalMany role cytoskeletal in the structural elements and functionalplay a vital organization role in the of structural mitochondria, and includingfunctional mitochondrial organization of shapemitochondria, and morphology, including dynamics, mitochon motility,drial shape and and mitosis morphology, [13–17]. Mostdynamics, importantly, motility, the and interaction mitosis [13– of mitochondria17]. Most importantly, with some the cytoskeletal interaction proteins of mitochondria and their connectionswith some cytoskeletal to voltage dependent proteins and anion their channelconnections (VDAC) to canvoltage be involved dependent in theanion coordination channel (VDAC) of mitochondrial can be involved function in [ 18the–23 coordination] (Figure1). of In themitochondrial heart, mitochondrial function [18–23] bioenergetics (Figure and 1). oxygenIn the heart, consumption mitochondrial are linearly bioenergetics dependent and on oxygen the cardiacconsumption contractile are activity linearly [24 ,dependent25] at rather on stable the concentrationcardiac contractile of the mainactivity mitochondrial [24,25] at rather regulator stable adenosineconcentration diphosphate of the main (ADP), mitochondrial which is a centralregulator element adenosine in mitochondrial diphosphate physiology.(ADP), which The is a exact central mechanismselement in of mitochondrial how mitochondria physiology. precisely The respond exact me tochanisms the heart of energy how mitochondria demand remained precisely unknown respond forto a the long heart time energy and require demand further remained investigations. unknown for A a lo growingng time bodyand require of evidence further shows investigations. that the A cellsgrowing contain body intracellular of evidence metabolic shows micro-compartments that the cells contain provided intracellular by multidirectional metabolic micro-compartments mitochondrial interactionsprovided withby multidirectional other subcellular mitochondrial organelles and macromolecules,interactions with in other particular, subcellular specific organelles cytoskeletal and proteinsmacromolecules, [26–34]. In in this particular, review, wespecific summarize cytoskeletal anddiscuss proteins previous [26–34]. studiesIn this review, that provide we summarize strong evidenceand discuss for the previous role of cytoskeletalstudies that provide proteins, strong in particular, evidence tubulin for thebeta-II role ofand cytoskeletal plectin 1b, proteins, in the in regulationparticular, of mitochondrialtubulin beta-II bioenergetics and plectin 1b, and in energythe regulation fluxes via of themitochondrial energy-transferring bioenergetics supercomplex and energy VDAC-mitochondrialfluxes via the creatineenergy-transferring kinase (MitCK)-ATP-ADP supercomplex translocase VDAC-mitochondrial (ANT) under physiological creatine andkinase pathological(MitCK)-ATP-ADP conditions. translocase (ANT) under physiological and pathological conditions. FigureFigure 1. The 1. centralThe central roles ofroles cytoskeleton of cytoskeleton and its interactions and its inte inractions mitochondrial in mitochondrial and entire cell and physiology. entire cell 2. Historicalphysiology. Retrospective 2. TheHistorical heart isRetrospective a high oxygen consuming and ATP demanding organ with a large number of mitochondria that occupy ~30% of cardiac cell volume. Besides supplying the cardiac tissue with ATP, mitochondriaThe heart play is an a importanthigh oxygen role consuming in cell signaling, and ATP diff erentiationdemanding andorgan growth, with asa large well asnumber in the of maintenancemitochondria of the that cellular occupy redox ~30% system, of cardiac ion homeostasis, cell volume. and Besides cell death, supplying actively the communicating cardiac tissue with with otherATP, cellular mitochondria systems likeplay SR an and important cytoskeleton. role in The cell presencesignaling, of differentiation micro-compartmentation and growth, of as ATP well and as in ADPthe (i.e., maintenance their high local of concentrationsthe cellular atredox mitochondria system, andion closehomeostasis, to myofibrils) and was cell evident death, from actively the observationscommunicating that cellular with bulkother concentrations cellular systems of ATP andlike ADPSR areand relatively cytoskeleton. constant, The independently presence of of changesmicro-compartmentation in heart workload. of Interestingly, ATP and ADP the total(i.e., ischemiatheir high or local anoxia concentrat quickly stopsions at heart mitochondria contractility and whileclose cellular to myofibrils) bulk ATP was concentration evident from decreases the observatio by onlyns ~5% that undercellular these bulk conditions. concentrations Furthermore, of ATP and theADP free cellularare relatively concentration constant, of independently ADP in the heart of changes (usually in ~20 heartµM) workload. cannot be Interestingly, higher than 50 theµ M,total otherwiseischemia it willor anoxia eventually quickly lead stops to the heart increased contractility left ventricular while cellular end diastolic bulk ATP pressure concentration and thus, decreases to the Cells 2020, 9, 222 3 of 24 cardiac rigor super-contracture.
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