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Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload.

ABSTRACT: Obesity leads to metabolic heart disease (MHD) that is associated with a pathologic increase in myocardial fatty acid (FA) uptake and impairment of mitochondrial function. The mechanism of mitochondrial dysfunction in MHD, which results in oxidant production and decreased energetics, is poorly understood but may be related to excess FAs. Determining the effects of cardiac FA excess on mitochondria can be hindered by the systemic sequelae of obesity. Mice with cardiomyocyte-specific overexpression of the fatty acid transport protein FATP1 have increased cardiomyocyte FA uptake and develop MHD in the absence of systemic lipotoxicity, obesity or diabetes. We utilized this model to assess 1) the effect of cardiomyocyte lipid accumulation on mitochondrial structure and energetic function and 2) the role of lipid-driven transcriptional regulation, signaling, toxic metabolite accumulation, and mitochondrial oxidative stress in lipid-induced MHD.Cardiac lipid species, lipid-dependent signaling, and mitochondrial structure/function were examined from FATP1 mice. Cardiac structure and function were assessed in mice overexpressing both FATP1 and mitochondrial-targeted catalase.FATP1 hearts exhibited a net increase (+12%) in diacylglycerol, with increases in several very long-chain diacylglycerol species (+160-212%, p<0.001) and no change in ceramide, sphingomyelin, or acylcarnitine content. This was associated with an increase in phosphorylation of PKC? and PKC?, and a decrease in phosphorylation of AKT and expression of CREB, PGC1?, PPAR? and the mitochondrial fusion genes MFN1, MFN2 and OPA1. FATP1 overexpression also led to marked decreases in mitochondrial size (-49%, p<0.01), complex II-driven respiration (-28.6%, p<0.05), activity of isolated complex II (-62%, p=0.05), and expression of complex II subunit B (SDHB) (-60% and -31%, p<0.01) in the absence of change in ATP synthesis. Hydrogen peroxide production was not increased in FATP1 mitochondria, and cardiac hypertrophy and diastolic dysfunction were not attenuated by overexpression of catalase in mitochondria in FATP1 mice.Excessive delivery of FAs to the cardiac myocyte in the absence of systemic disorders leads to activation of lipid-driven signaling and remodeling of mitochondrial structure and function.

SUBMITTER: Elezaby A

PROVIDER: S-EPMC4301992 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload.

Elezaby Aly A Sverdlov Aaron L AL Tu Vivian H VH Soni Kanupriya K Luptak Ivan I Qin Fuzhong F Liesa Marc M Shirihai Orian S OS Rimer Jamie J Schaffer Jean E JE Colucci Wilson S WS Miller Edward J EJ

Journal of molecular and cellular cardiology 20141209

<h4>Background</h4>Obesity leads to metabolic heart disease (MHD) that is associated with a pathologic increase in myocardial fatty acid (FA) uptake and impairment of mitochondrial function. The mechanism of mitochondrial dysfunction in MHD, which results in oxidant production and decreased energetics, is poorly understood but may be related to excess FAs. Determining the effects of cardiac FA excess on mitochondria can be hindered by the systemic sequelae of obesity. Mice with cardiomyocyte-spe ...[more]

PMID: 25497302

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Project description:RationaleLipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood.ObjectiveTo investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction.Methods and resultsMice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death.ConclusionsThese findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.

Project description:ObjectiveExploitation of protective metabolic pathways within injured myocardium still remains an unclarified therapeutic target in heart disease. Moreover, while the roles of altered fatty acid and glucose metabolism in the failing heart have been explored, the influence of highly dynamic and nutritionally modifiable ketone body metabolism in the regulation of myocardial substrate utilization, mitochondrial bioenergetics, reactive oxygen species (ROS) generation, and hemodynamic response to injury remains undefined.MethodsHere we use mice that lack the enzyme required for terminal oxidation of ketone bodies, succinyl-CoA:3-oxoacid CoA transferase (SCOT) to determine the role of ketone body oxidation in the myocardial injury response. Tracer delivery in ex vivo perfused hearts coupled to NMR spectroscopy, in vivo high-resolution echocardiographic quantification of cardiac hemodynamics in nutritionally and surgically modified mice, and cellular and molecular measurements of energetic and oxidative stress responses are performed.ResultsWhile germline SCOT-knockout (KO) mice die in the early postnatal period, adult mice with cardiomyocyte-specific loss of SCOT (SCOT-Heart-KO) remarkably exhibit no overt metabolic abnormalities, and no differences in left ventricular mass or impairments of systolic function during periods of ketosis, including fasting and adherence to a ketogenic diet. Myocardial fatty acid oxidation is increased when ketones are delivered but cannot be oxidized. To determine the role of ketone body oxidation in the remodeling ventricle, we induced pressure overload injury by performing transverse aortic constriction (TAC) surgery in SCOT-Heart-KO and ?MHC-Cre control mice. While TAC increased left ventricular mass equally in both groups, at four weeks post-TAC, myocardial ROS abundance was increased in myocardium of SCOT-Heart-KO mice, and mitochondria and myofilaments were ultrastructurally disordered. Eight weeks post-TAC, left ventricular volume was markedly increased and ejection fraction was decreased in SCOT-Heart-KO mice, while these parameters remained normal in hearts of control animals.ConclusionsThese studies demonstrate the ability of myocardial ketone metabolism to coordinate the myocardial response to pressure overload, and suggest that the oxidation of ketone bodies may be an important contributor to free radical homeostasis and hemodynamic preservation in the injured heart.

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Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload.

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Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload.

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