Characterization of cardiac effects of OPA1 protein promotion in transgenic animal model

Abstract

Abstract Introduction Mitochondria forms a dynamic network in cells, which is regulated by the balance between mitochondrial fusion and fission. The inhibition of mitochondrial fission could result in positive effects in acute ischemic/reperfusion injury models, due to prevention of mitochondrial membrane potential fall that goes along with fission processes. However, inhibition of fission in chronic models is disadvantageous because it obstructs the elimination of damaged mitochondrial fragments. OPA1 – in view of the previous results – a possible therapy target, as a fusion promoter and structure stabilizer protein. Methods We used transgenic mice in which OMA1 and YME1L cleavage spots of OPA1 were deleted. This resulted in higher representation of L-OPA1 compared to S-OPA1. After genotyping and model validation all animals were examined by echocardiograph and ECG on two occasions, at week 11 and 36. Histology samples were made from hearts, in case of mitochondrial morphology and structure remodelling examination. Cardiomyocytes were isolated from neonatal mice to determine the efficiency of mitochondrial respiration by SeaHorse assay method. Results Capillary Western immunoassay proved the presence and higher concentration of OPA1 in the TG animals. Echocardiographic examination showed a significant ejection fraction reduction in TG animals at week 36, but remodelling in histology samples could not be observed. The efficiency of mitochondrial respiration was decreased in TG animals compared to WT animals, according to the results of SeaHorse assay. Conclusion OPA1 protein promotion has a negative effect on systolic function during ageing. We confirmed that volume overload and ventricular remodeling did not manifested. The reason behind the loss of pump function might be at least partly the energy deficit due to the mitochondrial respiratory failure and the damage in mitochondrial quality control pathways. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The research in Hungary was funded by NKFIH within the framework of the project TKP2021-EGA-17.