Background:
Right heart failure (RHF) increases mortality in patients independent of the underlying disease. Therapeutic options, that directly target right ventricular (RV) dysfunction are not available. It is inevitable to understand RHF pathomechanisms to develop novel treatment strategies. We have recently identified that mitochondrial integrity is essential to maintain RV function upon pressure overload. Here, we aim to analyse the role of mitochondrial quality control in RV tissue of heart failure (HF) patients and in a mouse model with a loss-of-function point mutation in the gene encoding for the mitochondrial protease OMA1 (Oma1E324Q knock-in mice). Oma1E324Q knock-in is suggested to result in reduced cleavage of the mitochondrial GTPase OPA1, which may improve mitochondrial quality control and impact on mitochondrial fission/fusion dynamics.
Methods and Results:
RV pressure overload was induced in homozygous Oma1E324Q knock-in (OMA1) mice and wildtype (WT) littermates via pulmonary artery banding (PAB) for a period of 4 weeks (N=8/6). Western blot analyses of RV tissue confirmed the hypothesis that the ratio of long to short OPA1 (l-/s-OPA1) was significantly increased in OMA1 mice compared to WT both in control and PAB. In accordance, dynamin-like protein 1 (DLP1), which is also involved in fission/fusion dynamics, was increased in OMA1 mice as well. In contrast, levels of the mitochondrial outer membrane protein TOM70 increased upon PAB in both genotypes, reflecting enhanced fission upon PAB. Mitophagy, as reflected by LC3b-II/I protein ratio, was less abundant in OMA1 PAB mice compared to WT, which points towards a reduced need to degrade damaged mitochondria in OMA1 PAB. Transmission electron microscopy of RV tissue will shed light on potential differences on ultrastructural level. Echocardiography will disclose whether these processes relate to altered RV function.
To translate these findings to patients, RV tissue from explanted hearts of HF patients (N=21) was analysed and data were correlated with functional RV parameters. Interestingly, the l-/s-OPA1 ratio significantly correlated negatively with RV systolic pressure (p<0.05). In addition, the protein expression of mitofusion-1 (MFN1), a mitochondrial fusion protein, was less pronounced in patients with impaired RV function and also correlated negatively with RVSP (p<0.05). In addition, oxidative stress showed a significant negative correlation with TAPSE (p<0.05) and RV/PA coupling (p<0.01).
Conclusion:
Elevated RV afterload is associated with a disturbed mitochondrial quality control and RV dysfunction is associated with increased levels of oxidative stress. It needs to be investigated, whether modulation of mitochondrial quality control is a potential pharmacological target in RHF.
