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

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 ␣-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.

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

“…Previous data showed that mitochondrial dysfunction in mutant αB‐Crystallin mouse models of DRC correlated with opening of the MPTP and activation of apoptotic cell death 13, 30. MPTP opening results in mitochondrial swelling, eventually rupturing the outer mitochondrial membrane, releasing potent apoptogens into the cytoplasm and triggering apoptotic cell death.…”

“…DRC‐causing mutations result in early perturbations in mitochondrial structure. For example, mitochondrial disorganization was observed in the mutant αB‐crystallin Tg (CryAB R120G ) mouse models of DRC 10, 13, 14. In DRC mice expressing either D7‐Des or CryAB R120G , mitochondrial spatial organization was highly perturbed, and the myofibrils were interspersed with electron‐dense aggregates.…”

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

“…It is expected and already partially demonstrated that the misfolded R120GCRYAB participates in modified protein complexes (1,9,20,38,55), although a systematic analysis of this mutated interactome has not yet been described. In the context of this study, TrxR1 was the first candidate interactor to be tested to support the underlying hypothesis that such an interaction could contribute to enhancing TrxR1 activity in hR120GTg heart.…”

Molecular chaperones as regulators of cell death

“…Desminrelated myopathy is sometimes accompanied with cytosolic aggregated protein, including desmin and aBcrystallin (Vicart et al, 1998;Selcen and Engel, 2003). The biological characterization of aB-crystallin R120G mutation has indicated that mutant protein lose chaperone activity, form aggregation alone, perturb sarcomere architecture and lose antiapoptotic activity (Bova et al, 1999;Perng et al, 1999;Maloyan et al, 2005;Treweek et al, 2005;Simon et al, 2007). Myofibrillar myopathy is also found in homozygous deletion mouse of bag3, which is a member of the BAG family co-chaperone and a regulator of Hsp70 molecular chaperone.…”

“…The same group has used this transgenic mouse for analysing the biological effects of R120G mutation on apoptosis in vivo. Histological examination indicated that amyloidogenic oligomer was detected in the heart of R120G transgenic mouse, suggesting that toxic oligomer was generated by R120G mutation of aB-crystallin and causes apoptotic changes with mitochondrial dysfunction and disruption of the cytoskeletal network (Sanbe et al, 2004Maloyan et al, 2005).…”