LAUSR

Background: Previous studies show that mitochondrial network excitability, or the propagation of ROS signals, is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial network abnormality, the effect of mitochondrial-targeted antioxidant, such as mitoquinone (MitoQ), on mitochondrial network in pressure overload hearts has not been demonstrated. We hypothesize that MitoQ improves mitochondrial networks in HF via regulation of redox-related cardiac remodeling-associated non-coding RNAs. Methods and results: To test the hypothesis, C57BL/6J mice were subjected to ascending aortic constriction (AAC) to induce left ventricular (LV) pressure overload, followed by 7 days of MitoQ treatment (2 μmol). Doppler echocardiography revealed severe LV dilation and decreased ejection fraction following AAC, which were attenuated by MitoQ. Electron microscopy and immunostaining showed that inter-mitochondrial and mitochondria-sarcoplasmic reticulum (SR) network structure were altered in HF myocardium, in parallel with reduced expression of mitofusin proteins (e.g., MFN1 and MFN2) compared to sham-operated animals. MitoQ blunted mitofusin protein downregulation and improved mitochondrial networks. Our data also identified a MitoQ-mediated mechanism of mitofusin expression in HF by ameliorating the dysregulation of redox-related cardiac remodeling-associated long non-coding RNAs and microRNAs (i.e. Plscr4-miR-214 axis). Conclusion: The present study indicates that MitoQ improves inter-mitochondrial and mitochondrial-SR structural organization in pressure overload hearts by attenuating the dysregulation of cardiac remodeling-associated non-coding RNAs.