Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload

Abstract

Background 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. Methods 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. Results 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 PKCα and PKCδ, and a decrease in phosphorylation of AKT and expression of CREB, PGC1α, PPARα 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. Conclusions 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.

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

“…Increasing expression of PDK4 in the heart itself has not been reported to be pathologic in vivo [45] and has been shown to trigger an adaptive metabolic response [46]. Alterations in mitochondrial size and lipid accumulation have been associated with increased PPARα activation [47]. However, no changes in mitochondrial number and only minimal qualitative alterations were identified in MuRF1−/− hearts post-fenofibrate feeding up to 8 weeks (Fig.…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…Other lipid metabolism intermediates, namely diacylglycerols (DAGs) and ceramides, have been shown to interact with the insulin signalling pathway (Figure ), and their accumulation might lead to metabolic disturbances. The accumulation of DAGs increases protein kinase C (PKC)‐θ and PKC‐ε translocation in heart, following the reduction of Akt phosphorylation and decreased expression of mitochondrial fusion mediators . Ceramides inhibit Akt signalling via increased protein phosphatase 2 activity and activation of atypical PKC‐ζ .…”

Mitochondrial dysfunction and its impact on diabetic heart

“…A reduction in cardiac phosphocreatine/ATP ratios has also been demonstrated in hearts of diabetic patients with normal cardiac function by echocardiography [66, 67], suggesting that changes in mitochondrial function may precede the reduction in contractility. In another study, Anderson et al demonstrated in the left atrial appendage tissue from Type 2 diabetic patients undergoing coronary bypass surgery that mitochondrial respiratory function was impaired and hydrogen peroxide emission was increased, suggesting an increase in oxidative stress [68, 69]. Together with human data demonstrating altered lipid metabolism, these studies strongly implicate mitochondrial dysfunction in the human diabetic heart.…”