The ABA/LANCL1-2 hormone/receptors system controls cardiomyocyte mitochondrial function and ROS metabolism in cardiomyocytes through ERRα

Introduction: Abscisic acid (ABA) is a hormone conserved across kingdoms, including both modern plants and animals. In mammals, ABA interacts with two receptors, LANCL1 and LANCL2, and is involved in various tissue-specific physiological functions, such as regulating blood glucose levels, inflammation, cardiomyocyte energy metabolism, neuroprotection, controlling adipocyte browning and energy expenditure, and promoting hemopoietic stem cell regeneration [1-2]. Recently, we showed that rat H9c2 cardiomyocytes overexpressing ABA receptors exhibit an increased mitochondrial proton gradient, enhanced respiration, and improved vitality following hypoxia/reoxygenation [3]. Aims: The aims of this study were: (i) to investigate the role of the ABA/LANCL1-2 system in ROS content and metabolism in LANCL1/2-overexpressing versus LANCL1/2-silenced rat H9c2 cardiomyocytes; (ii) to explore a potential role of ERRα in the ABA/LANCL1-2 signaling pathway; and (iii) to identify new LANCL agonists. Methods: In LANCL1/2-overexpressing and -silenced H9c2 cells we assessed cell viability using the resazurin assay. measured lipid peroxidation and ROS content with specific fluorescence probes and evaluated the expression of radicals-generating and scavenging enzymes through qPCR and Western Blot analysis. Using Surface Plasmon Resonance analysis, we investigated the binding capacity and affinity between LANCL2 and AR42, a newly identified putative LANCL2 agonist as determined by molecular docking modeling. Results: LANCL1/2-overexpressing H9c2 cells have a significantly higher survival rate under a condition of oxidative stress with a higher expression of ROS-scavenging enzymes and show a reduced lipid hydroperoxides, mitochondrial ROS content and expression of ROS-generating enzymes compared with double-silenced cells, while maintaining a significantly steeper mitochondrial proton gradient [4]. The transcription factor ERRα. is involved in this effects. Preliminary results suggest that AR42 enhances the mitochondrial proton gradient in rat H9c2 cardiomyocytes and is a new LANCL2 agonist. Conclusion: The ABA/LANCL1-2 system regulates ROS turnover and emerges as a promising target for enhancing cardiomyocyte mitochondrial function and resilience to oxidative stress.