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Heart mitochondrial proteome study elucidates changes in cardiac energy metabolism and antioxidant PRDX3 in human dilated cardiomyopathy.

Roselló-Lletí E, Tarazón E, Barderas MG, Ortega A, Otero M, Molina-Navarro MM, Lago F, González-Juanatey JR, Salvador A, Portolés M, Rivera M - PLoS ONE (2014)

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.

ABSTRACT

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.

Methods and 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).

Conclusion: 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.

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Mitochondrial protein localization and overexpression in dilated human hearts analyzed using transmission electron microscopy.Influence of dilated cardiomyopathy on the amount and localization of the representative proteins involved in cardiac energy metabolism (ODPA, ETFD, DLDH, AL4A1, and ATPA), protein biosynthesis (EFTU), and stress response (PRDX3). We observed an increase in immunogold labeling in all proteins studied in DCM hearts. We also confirmed the location of all proteins analyzed and observed a similar distribution of each protein upon comparing pathological with control samples. The bar represents 100 nm. CNT, control; DCM, dilated cardiomyopathy; ODPA, pyruvate dehydrogenase E1 component subunit α, somatic form; ETFD, electron transfer flavoprotein-ubiquinone oxidoreductase; DLDH, dihydrolipoyl dehydrogenase; AL4A1, delta-1-pyrroline-5-carboxylate dehydrogenase; ATPA, ATP synthase subunit α; EFTU, elongation factor Tu; PRDX3, thioredoxin-dependent peroxide reductase.
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pone-0112971-g003: Mitochondrial protein localization and overexpression in dilated human hearts analyzed using transmission electron microscopy.Influence of dilated cardiomyopathy on the amount and localization of the representative proteins involved in cardiac energy metabolism (ODPA, ETFD, DLDH, AL4A1, and ATPA), protein biosynthesis (EFTU), and stress response (PRDX3). We observed an increase in immunogold labeling in all proteins studied in DCM hearts. We also confirmed the location of all proteins analyzed and observed a similar distribution of each protein upon comparing pathological with control samples. The bar represents 100 nm. CNT, control; DCM, dilated cardiomyopathy; ODPA, pyruvate dehydrogenase E1 component subunit α, somatic form; ETFD, electron transfer flavoprotein-ubiquinone oxidoreductase; DLDH, dihydrolipoyl dehydrogenase; AL4A1, delta-1-pyrroline-5-carboxylate dehydrogenase; ATPA, ATP synthase subunit α; EFTU, elongation factor Tu; PRDX3, thioredoxin-dependent peroxide reductase.

Mentions: Immunocytochemistry studies confirmed the previous results and the localization or distribution of these mitochondrial proteins. Figure 3 shows an increase in immunogold labeling in ODPA, ETFD, DLDH AL4A1, ATPA, EFTU, and PRDX3 in DCM hearts compared to CNT hearts. We observed similar localization of each protein in the pathological and CNT samples.


Heart mitochondrial proteome study elucidates changes in cardiac energy metabolism and antioxidant PRDX3 in human dilated cardiomyopathy.

Roselló-Lletí E, Tarazón E, Barderas MG, Ortega A, Otero M, Molina-Navarro MM, Lago F, González-Juanatey JR, Salvador A, Portolés M, Rivera M - PLoS ONE (2014)

Mitochondrial protein localization and overexpression in dilated human hearts analyzed using transmission electron microscopy.Influence of dilated cardiomyopathy on the amount and localization of the representative proteins involved in cardiac energy metabolism (ODPA, ETFD, DLDH, AL4A1, and ATPA), protein biosynthesis (EFTU), and stress response (PRDX3). We observed an increase in immunogold labeling in all proteins studied in DCM hearts. We also confirmed the location of all proteins analyzed and observed a similar distribution of each protein upon comparing pathological with control samples. The bar represents 100 nm. CNT, control; DCM, dilated cardiomyopathy; ODPA, pyruvate dehydrogenase E1 component subunit α, somatic form; ETFD, electron transfer flavoprotein-ubiquinone oxidoreductase; DLDH, dihydrolipoyl dehydrogenase; AL4A1, delta-1-pyrroline-5-carboxylate dehydrogenase; ATPA, ATP synthase subunit α; EFTU, elongation factor Tu; PRDX3, thioredoxin-dependent peroxide reductase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232587&req=5

pone-0112971-g003: Mitochondrial protein localization and overexpression in dilated human hearts analyzed using transmission electron microscopy.Influence of dilated cardiomyopathy on the amount and localization of the representative proteins involved in cardiac energy metabolism (ODPA, ETFD, DLDH, AL4A1, and ATPA), protein biosynthesis (EFTU), and stress response (PRDX3). We observed an increase in immunogold labeling in all proteins studied in DCM hearts. We also confirmed the location of all proteins analyzed and observed a similar distribution of each protein upon comparing pathological with control samples. The bar represents 100 nm. CNT, control; DCM, dilated cardiomyopathy; ODPA, pyruvate dehydrogenase E1 component subunit α, somatic form; ETFD, electron transfer flavoprotein-ubiquinone oxidoreductase; DLDH, dihydrolipoyl dehydrogenase; AL4A1, delta-1-pyrroline-5-carboxylate dehydrogenase; ATPA, ATP synthase subunit α; EFTU, elongation factor Tu; PRDX3, thioredoxin-dependent peroxide reductase.
Mentions: Immunocytochemistry studies confirmed the previous results and the localization or distribution of these mitochondrial proteins. Figure 3 shows an increase in immunogold labeling in ODPA, ETFD, DLDH AL4A1, ATPA, EFTU, and PRDX3 in DCM hearts compared to CNT hearts. We observed similar localization of each protein in the pathological and CNT samples.

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.

ABSTRACT

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.

Methods and 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).

Conclusion: 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.

Show MeSH
Related in: MedlinePlus