Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies

被引:162
作者
Sebastiani, Mariangela
Giordano, Carla
Nediani, Chiara.
Travaglini, Claudia
Borchi, Elisabetta
Zani, Massimo
Feccia, Mariano
Mancini, Massimiliano
Petrozza, Vincenzo
Cossarizza, Andrea
Gallo, Pietro
Taylor, Robert W.
d'Amati, Giulia
机构
[1] Univ Roma La Sapienza, Dipartimento Med Sperimentale, I-00161 Rome, Italy
[2] Univ Roma La Sapienza, Dipartimento Med Sperimentale, I-00161 Rome, Italy
[3] Univ Florence, Dipartimento Sci Biochim, Florence, Italy
[4] Azienda Osped S Camillo, Dipartimento Cardiochirurg, Rome, Italy
[5] Univ Modena & Reggio Emilia, Dipartimento Sci Biomed, Sez Patol Gen, Modena, Italy
[6] Newcastle Univ, Mitochondrial Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[7] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
基金
英国惠康基金;
关键词
D O I
10.1016/j.jacc.2007.06.035
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objectives 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.
引用
收藏
页码:1362 / 1369
页数:8
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