Mitochondrial dysfunction and apoptosis underlie the pathogenic process in α-B-crystallin desmin-related cardiomyopathy

Alina Maloyan, Atsushi Sanbe, Hanna Osinska, Margaret Westfall, Dustin Robinson, Ken Ichi Imahashi, Elizabeth Murphy, Jeffrey Robbins

Research output: Contribution to journalArticle

149 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3451-3461
Number of pages11
JournalCirculation
Volume112
Issue number22
DOIs
StatePublished - Nov 2005
Externally publishedYes

Fingerprint

Crystallins
Desmin
Cardiomyopathies
Cardiac Myocytes
Sarcomeres
Apoptosis
Mechanics
Heart Failure
Small Heat-Shock Proteins
Missense Mutation
Mutant Proteins
Amyloid
Adenoviridae
Oxygen Consumption
Membrane Potentials
Transgenic Mice
Transfection
Dilatation
Permeability
Mitochondria

Keywords

  • Cardiomyopathy
  • Heart diseases
  • Heart failure
  • Molecular biology

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mitochondrial dysfunction and apoptosis underlie the pathogenic process in α-B-crystallin desmin-related cardiomyopathy. / Maloyan, Alina; Sanbe, Atsushi; Osinska, Hanna; Westfall, Margaret; Robinson, Dustin; Imahashi, Ken Ichi; Murphy, Elizabeth; Robbins, Jeffrey.

In: Circulation, Vol. 112, No. 22, 11.2005, p. 3451-3461.

Research output: Contribution to journalArticle

Maloyan, A, Sanbe, A, Osinska, H, Westfall, M, Robinson, D, Imahashi, KI, Murphy, E & Robbins, J 2005, 'Mitochondrial dysfunction and apoptosis underlie the pathogenic process in α-B-crystallin desmin-related cardiomyopathy', Circulation, vol. 112, no. 22, pp. 3451-3461. https://doi.org/10.1161/CIRCULATIONAHA.105.572552
Maloyan, Alina ; Sanbe, Atsushi ; Osinska, Hanna ; Westfall, Margaret ; Robinson, Dustin ; Imahashi, Ken Ichi ; Murphy, Elizabeth ; Robbins, Jeffrey. / Mitochondrial dysfunction and apoptosis underlie the pathogenic process in α-B-crystallin desmin-related cardiomyopathy. In: Circulation. 2005 ; Vol. 112, No. 22. pp. 3451-3461.
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