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CLINICAL RESEARCH: CARDIOMYOPATHY

Induction of Mitochondrial Biogenesis Is a Maladaptive Mechanism in Mitochondrial Cardiomyopathies

Mariangela Sebastiani, BSc^_*, Carla Giordano, MD, PhD^_*, Chiara Nediani, BSc, Claudia Travaglini, BSc^_*, Elisabetta Borchi, BSc, Massimo Zani, BSc^_*, Mariano Feccia, MD, Massimiliano Mancini, MD^_*, Vincenzo Petrozza, MD, Andrea Cossarizza, MD^||, Pietro Gallo, MD^_*, Robert W. Taylor, PhD^# and Giulia d’Amati, MD, PhD^_*,_*

^_* Dipartimento di Medicina Sperimentale, Polo Pontino, Sapienza, Università di Roma, Rome, Italy
Dipartimento di Medicina Sperimentale, Polo Pontino, Sapienza, Università di Roma, Rome, Italy
Dipartimento di Scienze Biochimiche, Università di Firenze, Florence, Italy
Dipartimento di Cardiochirurgia, Azienda Ospedaliera S. Camillo, Rome, Italy
^|| Dipartimento di Scienze Biomediche, Sezione di Patologia Generale, Università di Modena e Reggio Emilia, Modena, Italy
^# Mitochondrial Research Group and Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom.

Manuscript received February 28, 2007; revised manuscript received May 11, 2007, accepted June 3, 2007.

^_* Reprint requests and correspondence: Dr. Giulia d’Amati, Dipartimento di Medicina Sperimentale, La Sapienza, Università di Roma, Viale Regina Elena 324, 00161 Rome, Italy. (Email: giulia.damati{at}uniroma1.it).

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.

Abbreviations and Acronyms   ANF = atrial natriuretic factor   DCM = dilated cardiomyopathy   GLUT = glucose transporter   GPX = glutathione peroxidase   IHD = ischemic heart disease   mCPT-I = carnitine palmitoyl transferase muscle isoform   MIC = maternally inherited cardiomyopathy   MnSOD = manganese superoxide dismutase   mtDNA = mitochondrial deoxyribonucleic acid   mt-tRNAIle = mitochondrial transfer ribonucleic acid isoleucine   NADPH = nicotinamide adenine dinucleotide 3-phosphate   PCR = polymerase chain reaction   PGC = peroxisome proliferator activated receptor coactivator   PPAR = peroxisome proliferator activated receptor   Tfam = transcription and mitochondrial DNA maintenance factor

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