Heart mitochondrial proteome study elucidates changes in cardiac energy metabolism and antioxidant PRDX3 in human dilated cardiomyopathy.
BACKGROUND
Dilated cardiomyopathy (DCM) is a public health problem with no available curative treatment, and mitochondrial dysfunction plays a critical role in its development. The present study is the first to analyze the mitochondrial proteome in cardiac tissue of patients with DCM to identify potential molecular targets for its therapeutic intervention.


RESULTS
16 left ventricular (LV) samples obtained from explanted human hearts with DCM (n = 8) and control donors (n = 8) were extracted to perform a proteomic approach to investigate the variations in mitochondrial protein expression. The proteome of the samples was analyzed by quantitative differential electrophoresis and Mass Spectrometry. These changes were validated by classical techniques and by novel and precise selected reaction monitoring analysis and RNA sequencing approach increasing the total heart samples up to 25. We found significant alterations in energy metabolism, especially in molecules involved in substrate utilization (ODPA, ETFD, DLDH), energy production (ATPA), other metabolic pathways (AL4A1) and protein synthesis (EFTU), obtaining considerable and specific relationships between the alterations detected in these processes. Importantly, we observed that the antioxidant PRDX3 overexpression is associated with impaired ventricular function. PRDX3 is significantly related to LV end systolic and diastolic diameter (r = 0.73, p value<0.01; r = 0.71, p value<0.01), fractional shortening, and ejection fraction (r = -0.61, p value<0.05; and r = -0.62, p value<0.05, respectively).


CONCLUSIONS
This work could be a pivotal study to gain more knowledge on the cellular mechanisms related to the pathophysiology of this disease and may lead to the development of etiology-specific heart failure therapies. We suggest new molecular targets for therapeutic interventions, something that up to now has been lacking.
Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
Esther
E
Roselló-Lletí
Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
Estefanía
E
Tarazón
Department of Vascular Physiopathology, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain.
María G
MG
Barderas
Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
Ana
A
Ortega
Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain.
Manuel
M
Otero
Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
Maria Micaela
MM
Molina-Navarro
Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain.
Francisca
F
Lago
Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain.
Jose Ramón
JR
González-Juanatey
Cardiology Service, Hospital La Fe, Valencia, Spain.
Antonio
A
Salvador
Cell Biology and Pathology Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
Manuel
M
Portolés
Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
Miguel
M
Rivera
D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D004452:Echocardiography; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D061105:Peroxiredoxin III / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000032:analysis*; D012313:RNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D000975:Antioxidants; D024101:Mitochondrial Proteins; D020543:Proteome; D012333:RNA, Messenger; D012313:RNA; D061105:Peroxiredoxin III