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Desmin Interacts Directly with Mitochondria

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Desmin Interacts Directly with Mitochondria International Journal of Molecular Sciences Article Desmin Interacts Directly with Mitochondria Alexander A. Dayal 1, Natalia V. Medvedeva 1, Tatiana M. Nekrasova 1, Sergey D. Duhalin 1, Alexey K. Surin 1,2 and Alexander A. Minin 1,* 1 Institute of Protein Research of Russian Academy of Sciences, Vavilova st., 34, 119334 Moscow, Russia; [email protected] (A.A.D.); [email protected] (N.V.M.); [email protected] (T.M.N.); [email protected] (S.D.D.); [email protected] (A.K.S.) 2 Pushchino Branch, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki 6, Pushchino, 142290 Moscow Region, Russia * Correspondence: [email protected] Received: 14 October 2020; Accepted: 26 October 2020; Published: 30 October 2020 Abstract: Desmin intermediate filaments (IFs) play an important role in maintaining the structural and functional integrity of muscle cells. They connect contractile myofibrils to plasma membrane, nuclei, and mitochondria. Disturbance of their network due to desmin mutations or deficiency leads to an infringement of myofibril organization and to a deterioration of mitochondrial distribution, morphology, and functions. The nature of the interaction of desmin IFs with mitochondria is not clear. To elucidate the possibility that desmin can directly bind to mitochondria, we have undertaken the study of their interaction in vitro. Using desmin mutant Des(Y122L) that forms unit-length filaments (ULFs) but is incapable of forming long filaments and, therefore, could be effectively separated from mitochondria by centrifugation through sucrose gradient, we probed the interaction of recombinant human desmin with mitochondria isolated from rat liver. Our data show that desmin can directly bind to mitochondria, and this binding depends on its N-terminal domain. We have found that mitochondrial cysteine protease can disrupt this interaction by cleavage of desmin at its N-terminus. Keywords: mitochondria; desmin; intermediate filaments; calpain 1. Introduction Intermediate filament (IF) networks are one of three cytoskeletal components along with microtubules and actin microfilaments. IFs provide mechanical strength and elasticity to cells and tissues and regulate intracellular positioning of nucleus and organelles [1]. It has been shown that one of the important roles of IFs inside animal cells is to ensure normal mitochondrial functioning [2–7]. Desmin, a major constituent of the IF network inside muscle cells, is a good example of such factors controlling mitochondria. A plethora of pathological conditions, collectively known as desminopathies, is caused by mutations in desmin and results in abnormalities in mitochondrial distribution and morphology as well as reduced mitochondrial respiratory function [5,7–9]. These data suggest that interaction with desmin is a prerequisite for normal mitochondrial functioning. However, the nature of interaction between desmin IFs and mitochondria is not fully elucidated. For example, one question that needs to be asked is whether desmin is able to bind directly to these organelles or some intermediary proteins are necessary. Previously, in G. Wiche’s lab, it was demonstrated that one such intermediary is plectin, particularly its 1b isoform, which interacts both with desmin and mitochondria [10]. However, experimental evidence showed certain desmin mutations which do not interfere with native IF structure or apparently with binding of plectin yet cause pathological conditions [11], including mitochondrial dysfunction [7]. A direct association between desmin IFs and mitochondria could explain these phenomena. In this study, we examined the possibility of a direct interaction between purified recombinant desmin and isolated rat liver mitochondria. We performed centrifugation in the sucrose Int. J. Mol. Sci. 2020, 21, 8122; doi:10.3390/ijms21218122 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 10 Int. J. Mol. Sci. 2020, 21, 8122 2 of 9 the possibility of a direct interaction between purified recombinant desmin and isolated rat liver mitochondria. We performed centrifugation in the sucrose gradient to separate desmin and a gradientheavier mitochondrial to separate desmin fraction. and a To heavier prevent mitochondrial sedimentation fraction. of unbound To prevent desmin, sedimentation we used of its unbound mutant desmin,form Des(Y122L). we used its This mutant point form mutation Des(Y122L). in desmin This arrests point mutationits polymerization in desmin at arrests the stage its polymerization of unit-length atfilaments the stage (ULFs) of unit-length consisting filaments of approximately (ULFs) consisting 30–40 ofpolypeptides approximately of desmin 30–40 polypeptides that are much of desminlighter thatthan arelong much IFs and lighter sediment than long only IFs at high-speed and sediment centrifugation. only at high-speed Figure centrifugation.1 shows that Des(Y122L) Figure1 shows when / thatexpressed Des(Y122L) in rat fibroblasts when expressed REF-52(Vim in rat− fibroblasts/−) devoid of REF-52(Vim IFs is unable− − )to devoid form filaments. of IFs is unableIt rather to forms form filaments.ULFs evenly It distributed rather forms throughout ULFs evenly the distributedcytoplasm, similarly throughout to mutant the cytoplasm, vimentin(Y117L) similarly [12,13]. to mutant vimentin(Y117L) [12,13]. / Figure 1. Immunofluorescence of REF-52(Vim− −) cells transfected with plasmid pIRES-EGFP- Des(Y122L).Figure 1. ExpressionImmunofluorescence of EGFP (left) andof desmin(Y122L) REF-52(Vim (right)−/−) cells in rat fibroblasttransfected stained with with antibodiesplasmid againstpIRES-EGFP-Des(Y122L). desmin shows evenly Expression distributed of unit-length EGFP (left) filaments and desmin(Y122L) (ULFs) but not long (right) intermediate in rat fibroblast filament (IF).stained Scale with 10 µantibodiesm. against desmin shows evenly distributed unit-length filaments (ULFs) but not long intermediate filament (IF). Scale 10 µm. Our results demonstrate that desmin in the form of ULFs binds to mitochondria directly, and the N-terminusOur results of its demonstrate molecule is responsiblethat desmin for in this the interaction.form of ULFs binds to mitochondria directly, and 2.the Results N-terminus of its molecule is responsible for this interaction. 2.1.2. Results Desmin Binds to Mitochondria In Vitro 2.1. DesminPreviously, Binds we to hypothesizedMitochondria In [6] Vitro that, similarly to vimentin, an N-terminal part of desmin molecule could contain a targeting signal which localizes desmin to the outer mitochondrial membrane (OMM). Its moderatelyPreviously, hydrophobic we hypothesized region spanning[6] that, fromsimilarly threonine-17 to vimentin, to proline-36 an N-terminal is flanked part by twoof desmin groups ofmolecule positively could charged contain amino a targeting acids—a characteristicsignal which patternlocalizes of manydesmin proteins to the known outer tomitochondrial be localized tomembrane OMM [14 (OMM).]. To predict Its moderately the presence hydrophobic of mitochondrial region targetingspanning peptidefrom threonine-17 in the molecule to proline-36 of human is desmin,flanked by we two used groups the online of positively program charged TargetP amino 1.1 [15 acids—a] to analyze characteristic its sequence pattern and of found many that proteins such signalknown is to present be localized with a highto OMM probability [14]. To (mTP—0.864). predict the presence Therefore, of accordingmitochondrial to the targeting analysis of peptide desmin’s in primarythe molecule structure, of human it belongs desmin, tothe we proteinsused the predisposed online program to localize TargetP in 1.1 mitochondria. [15] to analyze its sequence and foundTo test that the possibilitysuch signal of is the present direct with binding a high of desminprobability to mitochondria, (mTP—0.864). we Therefore, probed the according interaction to ofthe mitochondria analysis of desmin’s from a rat primary liver with structure, a recombinant it belongs human to the Des(Y122L) proteins predisposedin vitro. The to protein localize was in expressedmitochondria. and purified from bacterial lysate (see Supplementary Methods and Figure S1A). The bound Des(Y122L)To test was the determined possibility using of the Western direct blotting binding of mitochondrialof desmin to pellets mitochondria, obtained bywe centrifugation probed the ofinteraction their mixtures of mitochondria through sucrose fromcushion. a rat liver with a recombinant human Des(Y122L) in vitro. The proteinWhen was centrifuged expressed and through purified a sucrose from bacteria cushion,l lysate such desmin (see Supplementary mutant did not Methods sediment and by Figure itself andS1A). completely The bound stayed Des(Y122L) in the supernatant was determined (Figure 2usinA,B,g lines Western S1 and blotting P1). However, of mitochondrial when the samplepellets containedobtained by mitochondria, centrifugation some of their Des(Y122L) mixtures wasthrough found sucrose in the cushion. pellet, but only in the case where the proteaseWhen inhibitor centrifuged cocktail through was present a sucrose in thecushion, mixture such (Figure desmin2A,B, mutant lines S3did and not P3).sediment Incubation by itself of thisand proteincompletely with stayed mitochondria in the supernatant without protease (Figure inhibitors 2A,B, lines led S1 to and partial P1). protein However, degradation, when the andsample the shortenedcontained Des(Y122L)mitochondria, was some found Des(Y122L) only
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