Mitochondrial Dysfunction and Apoptosis Underlie the Pathogenic Process in α-B-Crystallin Desmin-Related Cardiomyopathy

Author:

Maloyan Alina1,Sanbe Atsushi1,Osinska Hanna1,Westfall Margaret1,Robinson Dustin1,Imahashi Ken-ichi1,Murphy Elizabeth1,Robbins Jeffrey1

Affiliation:

1. From the Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio (A.M., A.S., H.O., J.R.); University of Michigan, Ann Arbor; and Cardiac Surgery Section (M.W., D.R.) and Laboratory of Signal Transduction, National Institutes of Environmental Health Sciences (K.-I.I., E.M.); Research Triangle Park, NC.

Abstract

Background— Mitochondria and sarcomeres have a well-defined architectural relation that partially depends on the integrity of the cytoskeletal network. An R120G missense mutation in the small heat shock protein α-B-crystallin (CryAB) causes desmin-related cardiomyopathy. Desmin-related cardiomyopathy is characterized by the formation of intracellular aggregates containing CryAB and desmin that are amyloid positive, and disease can be recapitulated in transgenic mice by cardiac-specific expression of the mutant protein. Methods and Results— To understand the resultant pathology, we explored the acute effects of R120G expression both in vitro and in vivo. In vitro, transfection of adult cardiomyocytes with R120G-expressing adenovirus resulted in altered contractile mechanics. In vivo, as the cytoskeletal network is disturbed but before deficits in organ function can be detected, alterations in mitochondrial organization and architecture occur, leading to a reduction in the maximal rate of oxygen consumption with substrates that utilize complex I activity, alterations in the permeability transition pore, and compromised inner membrane potential. Apoptotic pathways are subsequently activated, which eventually results in cardiomyocyte death, dilation, and heart failure. Conclusions— Cardiac chaperone dysfunction acutely leads to altered cardiomyocyte mechanics, perturbations in mitochondrial-sarcomere architecture, and deficits in mitochondrial function, which can result in activation of apoptosis and heart failure.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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