The association of desmin with the α-crystallin Β-chain (αΒ-crystallin; encoded by CRYAB), and the fact that mutations in either one of them leads to heart failure in humans and mice, suggests a potential compensatory interplay between the two 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 found in most cardiomyopathies, with mitochondrial defects as a hallmark. We demonstrated that cardiac-specific αΒ-crystallin overexpression ameliorates all these defects and 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 (Δψm). Furthermore, we found that both desmin and αΒ-crystallin are localized at sarcoplasmic reticulum (SR)–mitochondria-associated membranes (MAMs), where they interact with VDAC, Mic60 – the core component of mitochondrial contact site and cristae organizing system (MICOS) complex – and ATP synthase, suggesting that these associations could be crucial in mitoprotection at different levels.
The authors declare no competing or financial interests.
A.D. designed and performed experiments, analyzed data and wrote the manuscript; E.S. and M.T. performed experiments; I.K. performed the electron microscopy experiments; M.M. and A. Vlahou performed and analyzed the proteomic experiments; S.G. helped with transgenic mice generation; A. Varela and C.H.D. performed and analyzed the echocardiography; Y.C. directed the research project, analyzed the data and wrote the manuscript. I.K. and M.T. made equal contributions to the work.
This work was supported by ESPA 2007-2013 grants from the Greek General Secretariat of Research and Development – Ministerium of Education [grant numbers PENED 01ED371, EPAN YB-22, PEP ATT-39 and ESPA 09SYN-21-965 to Y.C.], including a grant of Excellence II/ARISTEIA II 5342 (to Y.C.); a grant from the US National Institutes of Health [grant number RO1 AR39617 to Y.C.]; and in part by a European Commission grant [grant number FP7/REGPOT-2008-1 (Transmed)] to A.V. Deposited in PMC for release after 12 months.
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.192203.supplemental
- Received May 9, 2016.
- Accepted August 15, 2016.
- © 2016. Published by The Company of Biologists Ltd