MitoQ regulates redox-related noncoding RNAs to preserve mitochondrial network integrity in pressure-overload heart failure

Abstract

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day−1·mouse−1, 7 consecutive days) significantly ameliorated LV dysfunction, attenuated Mfn2 downregulation, improved interorganellar contact, and increased metabolism-related gene expression. Moreover, our data revealed that MitoQ alleviated the dysregulation of an Mfn2-associated lncRNA (i.e., Plscr4). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial intermitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructural remodeling in HF by maintaining Mfn2 expression via regulation by an lncRNA. These findings underscore the important role of lncRNAs in the pathogenesis of HF and the potential of targeting them for effective HF treatment. NEW & NOTEWORTHY We have shown that MitoQ improves cardiac mitochondrial network integrity and mitochondrial-SR alignment in a pressure-overload mouse heart-failure model. This may be occurring partly through preventing the dysregulation of a redox-sensitive lncRNA-microRNA pair (i.e., Plscr4-miR-214) that results in an increase in mitofusin-2 expression.

Oxidative Stress in Cardiovascular Diseases

“…For example, treatment of mice with mitoTEMPO reduces hypertension induced by both AngII or deoxycorticosterone acetate (DOCA) salt [76], reduces the mitochondrial superoxide anion and 3-nitrotyrosine, serum glucose levels and diastolic dysfunction observed in high-fat diet mice [34], decreases mitochondrial ROS production, and prevents cardiomyocytes hypertrophy in diabetic mouse hearts [77]. On the other hand, mitoquinone, which comprises an exogenous ubiquinone linked to a triphenylphosphonium lipophilic cation, was developed in 2001 [78] and has been demonstrated to effectively improve mitochondrial function and attenuate redox-related cardiomyopathies [36,79]. Moreover, some studies, notably in cancer cells, described that mitoquinone could also lead to ROS production, rapid membrane depolarization, and apoptotic cell death [80][81][82].…”

Mitochondrial Dysfunction and Heart Disease: Critical Appraisal of an Overlooked Association

“…Further investigations showed improved mitochondrial energetics in rats with pressure-overload HF [ 111 ], but no significant effect of mitoQ on cardiac function. More recently, mitoQ was shown to improve mitochondrial network dynamics (concerning both intermitochondrial and mitochondrion-to-sarcoplasmic reticulum alignment) in a similar HF model [ 112 ].…”

Mitochondria-Targeted Drug Delivery in Cardiovascular Disease: A Long Road to Nano-Cardio Medicine

“…In spontaneously hypertensive rats, 8 weeks of treatment with MitoQ reduced systolic blood pressure and attenuated cardiac hypertrophy [ 11 ]. Finally, in a mouse model of severe pressure overload, MitoQ ameliorated contractile dysfunction and improved mitochondrial network integrity and mitochondrial–sarcoplasmic reticulum (SR) alignment [ 12 , 13 ]. At the molecular level, MitoQ inhibited the noxious interplay between profibrotic factors and mitochondrially associated redox signaling while normalizing mitochondrial dynamics.…”

“…At the molecular level, MitoQ inhibited the noxious interplay between profibrotic factors and mitochondrially associated redox signaling while normalizing mitochondrial dynamics. Interestingly, MitoQ rescued the dysregulation of several redox-sensitive noncoding RNAs associated with cardiac remodeling such as the pro-hypertrophic long non-coding RNA cardiac hypertrophy-associated transcript (Chast), the anti-hypertrophic long non-coding RNA my-heart (Mhrt), and the long non-coding Plscr4/miRNA-214 axis [ 12 , 13 ]. Given the increasing importance of non-coding RNA species in the pathophysiology of the cardiovascular system, these findings highlight a previously unappreciated therapeutic potential of MitoQ to contrast the evolution of HF.…”