J Cell Sci.2016 Oct;129(20):3705-3720

Desmin and alpha B-crystallin interplay in the maintenance of mitochondrial homeostasis and cardiomyocyte survival.

Antigoni Diokmetzidou1*, Elisavet Soumaka1*, Ismini Kloukina1, Manousos Makridakis2, Emilia Varela3, Constantinos H. Davos3, Vasiliki Anesti1, Antonia Vlachou2, and Yassemi Capetanaki1,&

 

1 Center of Basic Research, 2Center of Systems Biology, 3,Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece

 

* Contributed equally

& Corresponding author:

Yassemi Capetanaki

Center of Basic Research

Biomedical Research Foundation

Academy of Athens

11527 Athens, Greece

Tel: +30-210-6597212

Fax: +30-210-6597545

e-mail: ycapetanaki@bioacademy.gr

  

Abstract

The association of desmin with αΒ-Crystallin, and the fact that mutations in either one of them lead to heart failure in humans and mice, suggests a potential compensatory interplay between them in cardioprotection. To address this hypothesis, we investigated the consequences of αΒ-Crystallin overexpression in the desmin deficient (des-/-) mouse model, which possesses a combination of the pathologies of most cardiomyopathies, with mitochondrial defects as a hallmark. We demonstrated that cardiac specific αΒ-Crystallin overexpression ameliorates all these defects and significantly improves cardiac function to almost wild type levels. Protection by αΒ-Crystallin overexpression is linked to maintenance of proper mitochondrial protein levels, inhibition of abnormal mitochondrial permeability transition pore activation and maintenance of mitochondrial membrane potential (Δψ). Furthermore, we found that both desmin and αΒ-crystallin are localized at SR-mitochondria associated membranes, where they interact with VDAC, MICOS (contact site and cristae organizing system) complex and ATP synthase, suggesting that these associations could be crucial in mitoprotection at different levels.

KEYWORDS: Cristae; Cytoskeleton; Heart failure; Intermediate filaments; MAMs; Mitochondria; Small heat-shock protein

PMID: 27566162

 

Supplements:

The present work highlights the importance of the intermediate filament protein desmin network and its interacting protein αB-crystallin in the maintenance of a healthy and properly energized cardiac muscle. It demonstrated that αB-Crystallin, a small heat shock protein, is an excellent therapeutic target for heart failure, given that it provided an unprecedented improvement to the highly defected desmin deficient heart, to almost wild type (wt) levels. The association of αB-crystallin to cytoskeletal proteins has been widely shown (1,2) and its chaperone activity (3), including that for cytoskeletal proteins (2), is one of the first protective functions attributed to it. As a consequence, αB-crystallin is detected along with many cytoskeletal and cytoskeleton associated proteins in aggregates in multiple diseases (4,5,6,7). This work provides evidence that the desmin network is in turn necessary for efficient protection of the myocardium by the endogenous levels of αB-crystallin. In the desmin deficient myocardium, however, a much greater quantity of αB-crystallin is needed to achieve the same levels of protection as in the wt heart. Both desmin and αB-crystallin were found to the hot spot of MAMs (the mitochondria associated membranes of the sarcoplasmic reticulum) providing a possible mechanism of cardioprotection by desmin cytoskeleton. Their association there with proteins important for proper mitochondrial morphology, homeostasis and function seems to be valuable for cardiomyocyte survival and maintenance of well functioning heart. Moreover, αB-crystallin overexpression in the desmin deficient heart managed to keep in balance the cardiac metabolism by maintaining the proper levels of many mitochondrial enzymes, diminished in the desmin deficient heart, which provide the equivalents for efficient ATP production and antioxidant function. The extended mitochondrial protection offered by αB-crystallin makes it an excellent candidate for the treatment of a continuously increasing list of degenerative diseases linked to protein aggregation and mitochondrial abnormalities.

 

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