Abstract
Maintenance of a healthy pool of mitochondria is important for the function and survival of terminally differentiated cells such as cardiomyocytes. Epoxyeicosatrienoic acids (EETs) are epoxy lipids derived from metabolism of arachidonic acid by cytochrome P450 epoxygenases. We have previously shown that EETs trigger a protective response limiting mitochondrial dysfunction and reducing cellular death. The aim of this study was to investigate whether EET-mediated effects influence mitochondrial quality in HL-1 cardiac cells during starvation. HL-1 cells were subjected to serum- and amino acid free conditions for 24h. We employed a dual-acting synthetic analog UA-8 (13-(3-propylureido)tridec-8-enoic acid), possessing both EET-mimetic and soluble epoxide hydrolase (sEH) inhibitory properties, or 14,15-EET as model EET molecules. We demonstrated that EET-mediated events significantly improved mitochondrial function as assessed by preservation of the ADP/ATP ratio and oxidative respiratory capacity. Starvation induced mitochondrial hyperfusion observed in control cells was attenuated by UA-8. However, EET-mediated events did not affect the expression of mitochondrial dynamic proteins Fis1, DRP-1 or Mfn2. Rather we observed increased levels of OPA-1 oligomers and increased mitochondrial cristae density, which correlated with the preserved mitochondrial function. Increased DNA binding activity of pCREB and Nrf1/2 and increased SIRT1 activity together with elevated mitochondrial proteins suggest EET-mediated events led to preserved mitobiogenesis. Thus, we provide new evidence for EET-mediated events that preserve a healthier pool of mitochondria in cardiac cells following starvation-induced stress.
Highlights
Mitochondria provide the primary source of energy that fuels the contractile apparatus within the heart and have a key role in regulating cellular death pathways
Prolonged cellular starvation causes significant cellular damage resulting in the existence of an unhealthy pool of mitochondria
We demonstrated that HL-1 cardiac cells treated with EETs had better cell survival following 24h of starvation [31]
Summary
Mitochondria provide the primary source of energy that fuels the contractile apparatus within the heart and have a key role in regulating cellular death pathways. These dynamic organelles respond to changes in cellular energy demands and stress levels [1,2,3]. Mitochondrial quality control is maintained through precise coordination of a complex interplay between mitobiogenesis and selective degradation of through autophagic processes. Dysfunctional mitochondria disturb the energetic balance in the myocardium and can initiate cell death [6]. The removal of dysfunctional mitochondria is an important process to maintain a robust mitochondrial network within the cardiomyocyte [7, 8]. Optimum mitochondrial health is vital for cardiomyocyte performance and resistance to stress
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