title: Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-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 alpha-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.
  
  
  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.
authors.affiliation: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Maloyan
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Margaret
authors.initials: M
authors.lastname: Westfall
authors.forename: Dustin
authors.initials: D
authors.lastname: Robinson
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Imahashi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000682:Amyloid; D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D003893:Desmin / Q000502:physiology*; D019281:Dimerization; D006801:Humans; D007473:Ion Channels; D051379:Mice; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology; D051381:Rats; D014162:Transfection; D038203:alpha-Crystallin B Chain / Q000235:genetics*
chemical_list: D000682:Amyloid; D003893:Desmin; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D038203:alpha-Crystallin B Chain