Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish.

Deung-Dae Park,Julia Krause,Wolfgang Rottbauer,Bernd M Gahr,Steffen Just,Tanja Zeller

doi:10.3390/ijms22168468

Abstract

In the human heart, the energy supplied by the production of ATP is predominately accomplished by ß-oxidation in mitochondria, using fatty acids (FAs) as the primary fuel. Long-chain acylcarnitines (LCACs) are intermediate forms of FA transport that are essential for FA delivery from the cytosol into mitochondria. Here, we analyzed the impact of the LCACs C18 and C18:1 on mitochondrial function and, subsequently, on heart functionality in the in vivo vertebrate model system of zebrafish (Danio rerio). Since LCACs are formed and metabolized in mitochondria, we assessed mitochondrial morphology, structure and density in C18- and C18:1-treated zebrafish and found no mitochondrial alterations compared to control-treated (short-chain acylcarnitine, C3) zebrafish embryos. However, mitochondrial function and subsequently ATP production was severely impaired in C18- and C18:1-treated zebrafish embryos. Furthermore, we found that C18 and C18:1 treatment of zebrafish embryos led to significantly impaired cardiac contractile function, accompanied by reduced heart rate and diminished atrial and ventricular fractional shortening, without interfering with cardiomyocyte differentiation, specification and growth. In summary, our findings provide insights into the direct role of long-chain acylcarnitines on vertebrate heart function by interfering with regular mitochondrial function and thereby energy allocation in cardiomyocytes.

Highlights

By treating embryos with the different compounds, we found that 5 μM of C18 resulted in significantly increased mortality of zebrafish embryos, whereas 5 μM of C18:1 and C3-treated embryos (C3) had no negative effects on embryo survival (Figure 2B)
We found that the mitochondrial structure in cardiomyocytes was not altered in C18- and C18:1-treated zebrafish embryos compared to control-treated (C3) or wild-type embryos (Figure 4C–H and Supplementary Figure S2A)
long-chain acylcarnitines (LCACs) in the adenosine triphosphate (ATP) production of mitochondria, we observed significantly reduced mitocorrelated to the stage and severity of the disease, whereas a putative direct impact chondrial function and ATP levels in treated embryos, whereas the morphology, structure of

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mitochondrial dysfunction has been implicated in the development of heart failure, which is the leading cause of hospitalization in all Western countries and is associated with high morbidity and mortality. Mitochondrial dysfunction often develops as the result of unsuccessful adaptation to energy stress in the heart, which perpetuates a maladaptive spiral, augmenting cardiac damage. Heart failure was found to be linked to defective carnitine transport and mitochondrial fatty acid (FA) oxidation [1]. Cardiac mitochondrial FA oxidation is a pivotal pathway for maintaining energy homeostasis and is a significant source of adenosine triphosphate (ATP) energy provision under restricted glucose accessibility. Due to an impermeable inner mitochondrial membrane, free long-chain

Methods

Results

Conclusion