title: Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies.
abstract: OBJECTIVE
  The purpose of this study was to clarify the molecular mechanisms linking human mitochondrial deoxyribonucleic acid (mtDNA) dysfunction to cardiac remodeling.
  
  
  BACKGROUND
  Defects of the mitochondrial genome cause a heterogeneous group of clinical disorders, including mitochondrial cardiomyopathies (MIC). The molecular events linking mtDNA defects to cardiac remodeling are unknown. Energy derangements and increase of mitochondrial-derived reactive oxygen species (ROS) could both play a role in the development of cardiac dysfunction in MIC. In addition, mitochondrial proliferation could interfere with sarcomere alignment and contraction.
  
  
  METHODS
  We performed a detailed morphologic and molecular analysis on failing hearts from 3 patients with MIC, failing human hearts due to ischemic heart disease (IHD) or dilated cardiomyopathies (DCM), and nonfailing hearts.
  
  
  RESULTS
  The MIC hearts showed marked mitochondrial proliferation with myofibril displacement. Consistent with morphologic features, increase in mtDNA content per cell and induction of genes involved in mitochondrial biogenesis, fatty acid metabolism, and glucose transport were observed. Down-regulation of these genes characterized DCM and IHD hearts. A pronounced increase in mitochondrial-derived ROS was observed in MIC hearts compared with failing hearts due to other causes. This was paralleled by up-regulation of genes encoding for uncoupling proteins and antioxidant enzymes. However, there was not a significant increase in antioxidant enzyme activity.
  
  
  CONCLUSIONS
  Our results suggest that besides energy deficiency, mitochondrial biogenesis per se is a maladaptive response in MIC and, possibly, in other metabolic cardiomyopathies.
authors: Dipartimento di Medicina Sperimentale, Polo Pontino, Sapienza, Università di Roma, Rome, Italy.
authors: Mariangela
authors: M
authors: Sebastiani
authors: Carla
authors: C
authors: Giordano
authors: Chiara
authors: C
authors: Nediani
authors: Claudia
authors: C
authors: Travaglini
authors: Elisabetta
authors: E
authors: Borchi
authors: Massimo
authors: M
authors: Zani
authors: Mariano
authors: M
authors: Feccia
authors: Massimiliano
authors: M
authors: Mancini
authors: Vincenzo
authors: V
authors: Petrozza
authors: Andrea
authors: A
authors: Cossarizza
authors: Pietro
authors: P
authors: Gallo
authors: Robert W
authors: RW
authors: Taylor
authors: Giulia
authors: G
authors: d'Amati
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D015415:Biomarkers; D013481:Superoxides; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase