Altered Cardiolipin Metabolism is Associated with Cardiac Mitochondrial Dysfunction in Pulmonary Vascular Remodeled Perinatal Rat Pups

AbstractBackgroundPulmonary vascular remodeling (PVR) in utero results in the development of heart failure (HF). The alterations that occur in cardiac lipid and mitochondrial bioenergetics during the development of in utero PVR was unknown.MethodsPVR was induced in pups in utero by exposure of pregnant dams to indomethacin and hypoxia. Cardiac lipids, echocardiographic function and cardiomyocyte mitochondrial function were subsequently examined.ResultsPerinatal rat pups with PVR exhibited elevated left and right cardiac ventricular internal dimensions and reduced ejection fraction and fractional shortening compared to controls. Cardiac myocytes from these pups exhibited increased glycolytic capacity and glycolytic reserve compared to controls. However, respiration with glucose as substrate was unaltered. Fatty acid oxidation and ATP-insensitive respiration were increased in isolated cardiac myocytes from these pups compared to controls indicating mitochondrial dysfunction. Although abundance of mitochondrial respiratory complexes were unaltered, increased trilinoleoyl-lysocardiolipin levels in these pups was observed. A compensatory increase in both cardiolipin (CL) and phosphatidylethanolamine (PE) content were observed due to increased synthesis of these phospholipids.ConclusionAlterations in cardiac cardiolipin and phospholipid metabolism in PVR rat pups is associated with the mitochondrial bioenergetic and cardiac functional defects observed in their hearts.Impact statement- Phospholipid metabolism was examined in pulmonary vascular remodeling in perinatal rat pups.- Pulmonary vascular remodeling was induced in utero by treating pregnant dams with hypoxia and indomethacin at 19-21 days of gestation.- The offspring exhibited altered pulmonary arterial remodeling with subsequent cardiac hypertrophy, ventricular dysfunction, cardiac myocyte mitochondrial dysfunction with altered fatty acid utilization.- In addition, the offspring exhibited elevated cardiolipin, lysocardiolipin and phosphatidylethanolamine content which may potentially contribute to the cardiac mitochondrial dysfunction.

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Faculty Opinions recommendation of Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4848963.4889054 ◽

2010 ◽

Author(s):

Fabio Recchia ◽

Vincenzo Lionetti

Keyword(s):

Pulmonary Hypertension ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Vascular Remodeling ◽

Acid Oxidation ◽

Malonyl Coa

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Abstract 331: Recovery of Mitochondrial Bioenergetics after Hypoxia via Regulating Pyruvate Dehydrogenase Kinase and Adenosine Monophosphate-activated Kinase

Circulation Research ◽

10.1161/res.115.suppl_1.331 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Jessica M Toli ◽

Minzhen He ◽

Carolyn Suzuki ◽

Maha Abdellatif

Keyword(s):

Fatty Acid ◽

Oxidative Phosphorylation ◽

Cardiac Myocytes ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Kinase ◽

Neonatal Rat ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Mitochondrial Bioenergetics ◽

Peroxisome Proliferator Activated Receptor

Mitochondrial quality control is critical for the survival of cardiac myocytes during stress. The purpose of this study was to examine the effect of metabolic substrates and regulators of metabolism on mitochondrial bioenergetics, as an indicator of mitochondrial quality, and how these factors might influence the recovery of the cell’s bioenergetics after hypoxia/ischemia. By monitoring oxygen consumption rates (OCR), in real-time, in live neonatal rat myocytes and human cardiac myocyte-differentiated induced pluripotent stem cells, we found that both cell types can maintain basal OCR efficiently with any metabolic substrate; however, the neonatal cells require both glucose and fatty acid, while the human adult cells require fatty acid only, for mounting maximum reserve respiratory capacity (RRC). Our data also show that subjecting cardiac myocytes to hypoxia results in a reduction of the cells’ basal OCR and oxidative phosphorylation, and exhausts the RRC, which is accompanied by an increase in pyruvate dehydrogenase kinase (Pdk) 1 and 4. Except for normalization of Pdk1 levels, there was little or no recovery of these parameters after reoxygenation. We, thus, hypothesized, that inhibition of Pdks may help recovery of the cell’s bioenergetics. Indeed, our results show that by inhibiting Pdks with dichloroacetate (DCA) before or after hypoxia, the cells’ bioenergetics, including OCR, oxidative phosphorylation, and RRC in neonatal myocytes, and RRC in the human myocytes fully recover within 24 h. On the other hand, activating AMP-activated kinase (AMPK) resulted in delayed (96 h) improvement of the cells’ RRC that was accompanied by an increase in peroxisome proliferator-activated receptor gamma, coactivator 1α (3.5x), peroxisome proliferator-activated receptor-α (2x), and mitochondrial number (2x). These results led us to conclude that compromised mitochondrial quality can be rescued through mechanisms that regulate glucose or fatty acid oxidation by either inhibiting Pdks or activating AMPK, respectively, in rodent and human myocytes.

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Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1471-y ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 15

Author(s):

Jin Seok ◽

Hyun Sook Jung ◽

Sohae Park ◽

Jung Ok Lee ◽

Chong Jai Kim ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Fatty Acid ◽

Mitochondrial Dysfunction ◽

Fatty Acid Oxidation ◽

Replicative Senescence ◽

Acid Oxidation ◽

Differentiation Potential ◽

Passage Number

Abstract Background Human placenta-derived mesenchymal stem cells (PD-MSCs) are powerful sources for cell therapy in regenerative medicine. However, a limited lifespan by senescence through mechanisms that are well unknown is the greatest obstacle. In the present study, we first demonstrated the characterization of replicative senescent PD-MSCs and their possible mitochondrial functional alterations. Methods Human PD-MSCs were cultured to senescent cells for a long period of time. The cells of before passage number 8 were early cells and after passage number 14 were late cells. Also, immortalized cells of PD-MSCs (overexpressed hTERT gene into PD-MSCs) after passage number 14 were positive control of non-senescent cells. The characterization and mitochondria analysis of PD-MSCs were explored with long-term cultivation. Results Long-term cultivation of PD-MSCs exhibited increases of senescent markers such as SA-β-gal and p21 including apoptotic factor, and decreases of proliferation, differentiation potential, and survival factor. Mitochondrial dysfunction was also observed in membrane potential and metabolic flexibility with enlarged mitochondrial mass. Interestingly, we founded that fatty acid oxidation (FAO) is an important metabolism in PD-MSCs, and carnitine palmitoyltransferase1A (CPT1A) overexpressed in senescent PD-MSCs. The inhibition of CPT1A induced a change of energy metabolism and reversed senescence of PD-MSCs. Conclusions These findings suggest that alteration of FAO by increased CPT1A plays an important role in mitochondrial dysfunction and senescence of PD-MSCs during long-term cultivation.

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Fatty Acid Oxidation and Malonyl-CoA Decarboxylase in the Vascular Remodeling of Pulmonary Hypertension

Science Translational Medicine ◽

10.1126/scitranslmed.3001327 ◽

2010 ◽

Vol 2 (44) ◽

pp. 44ra58-44ra58 ◽

Cited By ~ 131

Author(s):

G. Sutendra ◽

S. Bonnet ◽

G. Rochefort ◽

A. Haromy ◽

K. D. Folmes ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Vascular Remodeling ◽

Acid Oxidation ◽

Malonyl Coa

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Nox4 Regulates Glycolysis and Fatty Acid Oxidation in Cardiac Myocytes

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2015.10.160 ◽

2015 ◽

Vol 87 ◽

pp. S60-S61

Author(s):

Anna Zoccarato ◽

Adam A Nabeebaccus ◽

Ajay MShah

Keyword(s):

Fatty Acid ◽

Cardiac Myocytes ◽

Fatty Acid Oxidation ◽

Acid Oxidation

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Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

Frontiers in Immunology ◽

10.3389/fimmu.2021.755862 ◽

2021 ◽

Vol 12 ◽

Author(s):

João Paulo Silva Nunes ◽

Pauline Andrieux ◽

Pauline Brochet ◽

Rafael Ribeiro Almeida ◽

Eduardo Kitano ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Mitochondrial Dysfunction ◽

Chagas Disease ◽

Nitrosative Stress ◽

Acid Oxidation ◽

Oxidative And Nitrosative Stress ◽

Human Cardiomyocytes ◽

Tnf Α ◽

Ifn Γ

Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes’ mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy.

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Development of independent ingestive responding to blockade of fatty acid oxidation in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.5.r1649 ◽

1997 ◽

Vol 273 (5) ◽

pp. R1649-R1656 ◽

Cited By ~ 1

Author(s):

Susan E. Swithers

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

The Other ◽

Acid Oxidation ◽

Low Doses ◽

Rat Pups ◽

Carnitine Palmitoyltransferase I ◽

Metabolic Signal ◽

Cpt I ◽

Acyl Coenzyme A

The present studies examined the development of ingestive responsiveness to blockade of fatty acid oxidation in rat pups using 2-mercaptoacetate (MA), an inhibitor of mitochondrial acyl-coenzyme A dehydrogenases, or methyl palmoxirate (MP), an inhibitor of carnitine palmitoyltransferase I (CPT-I). Rat pups aged 6, 9, 12, or 15 days of age received an intraperitoneal injection of 0, 100, 200, 400, or 800 μmol/kg MA, and intake of a commercial half-and-half or 15% glucose diet from the floor of test containers was assessed in a 30-min test beginning 1 h after administration of MA. The results demonstrate that, although no dose of MA affected intake of either diet in pups 9 days or younger, low doses of MA increased intake and the highest dose suppressed intake of both diets in pups 12 days of age or older. Physiological measurements indicated that levels of β-hydroxybutyrate were significantly lower following doses of 400 or 800 μmol/kg MA in 9-, 12-, and 15-day-old pups and that gastric emptying was inhibited in 12 and 15 day olds by 800 μmol/kg MA. Intake of a commercial half-and-half diet from the floor of test containers was also assessed in 12- to 18-day-old rat pups 6.5 h after they received a gavage load of 0, 1.25, 2.5, 5, or 10 mg/kg MP. Unlike MA, MP did not increase intake of a commercial half-and-half diet in rat pups 12 or 15–18 days of age; instead, the highest dose of MP suppressed intake in 15- to 18-day-old pups. The failure of MP to enhance intake in pups at the ages tested is likely related to composition of dam’s milk; rat milk is high in medium-chain fatty acids that do not require CPT-I for entry into mitochondria. Thus it is likely that MP does not significantly block fatty acid oxidation in pups at the ages tested. On the other hand, blockade of fatty acid oxidation produced by MA significantly affects intake by 12 days of age, suggesting it may be the first metabolic signal that influences intake in rat pups.

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