MiR-485-5p modulates mitochondrial fission through targeting mitochondrial anchored protein ligase in cardiac
Yanfang Zhao1, Murugavel Ponnusamy1, Cuiyun Liu1
1Center for Developmental Cardiology, Institute for Translational Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China.
Abstract:
The pathogenesis of cardiac hypertrophy is tightly associated with mitochondrial dysfunction. Disequilibrium of mitochondrial dynamic is one of the main drivers in the pathological processes during development of various cardiac diseases. However, the effect of mitochondrial dynamics on cardiac hypertrophy remains largely unclear. MicroRNAs (miRNAs) are small noncoding RNAs that can switch off expression of many genes. Mitochondrial anchored protein ligase (MAPL) is a small ubiquitin-like modifier (SUMO) E3 ligase, which is an important contributor in mitochondrial fission process. In this study, we found that hypertrophic agonist phenylephrine (PE) enhanced the expression of MAPL and promoted mitochondrial fission, while it decreased the expression of mitochondrial fusion protein2 (Mfn2) in hypertrophic cardiomyocytes. Silencing expression of MAPL by siRNA attenuated PE-induced depletion of Mfn2 and increase of mitochondrial fission as well as hypertrophic response in cultured primary cardiomyocytes. MiR-485-5p is screened as a candidate inhibitor of MAPL. Overexpression of miR-485-5p blocked mitochondrial fission and hypertrophy induced by PE through inhibiting MAPL expression and increasing the level of Mfn2 in cultured primary cardiomyocytes. In mice model of cardiac hypertrophy induced by PE, the administration of miR-485-5p agomir significantly decreased the PE induced increase in the expression of MAPL and hypertrophic markers (ANP and β-MHC) along with protection of cardiac structure and function. Together, this study exhibits a novel signaling axis composed of miR-485-5p/MAPL/Mfn2, which regulates mitochondrial machinery and cardiac hypertrophy.
Insights
This study reveals a new pathway involving miR-485-5p, MAPL, and Mfn2 that controls mitochondrial dynamics and cardiac hypertrophy. Targeting this axis may offer new treatments for heart disease.
Area of Science:
- Cardiology
- Molecular Biology
- Mitochondrial Biology
Background:
- Cardiac hypertrophy is linked to mitochondrial dysfunction and altered mitochondrial dynamics.
- The specific role of mitochondrial dynamics in cardiac hypertrophy pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of mitochondrial dynamics, specifically mitochondrial fission and fusion proteins, in cardiac hypertrophy.
- To identify key molecular regulators, including microRNAs, involved in this process.
Main Methods:
- Utilized cultured primary cardiomyocytes and a mouse model of cardiac hypertrophy induced by phenylephrine (PE).
- Investigated the expression of mitochondrial anchored protein ligase (MAPL) and mitochondrial fusion protein 2 (Mfn2).
- Employed siRNA to silence MAPL and agomir to overexpress miR-485-5p.
Main Results:
- PE treatment increased MAPL expression, promoted mitochondrial fission, and decreased Mfn2 expression in cardiomyocytes.
- MAPL silencing attenuated PE-induced mitochondrial changes and hypertrophic responses.
- miR-485-5p was identified as a MAPL inhibitor; its overexpression reduced mitochondrial fission and hypertrophy by increasing Mfn2 levels.
- In vivo, miR-485-5p agomir administration reduced MAPL and hypertrophic markers, preserving cardiac structure and function.
Conclusions:
- A novel signaling axis (miR-485-5p/MAPL/Mfn2) regulates mitochondrial dynamics and cardiac hypertrophy.
- This axis presents a potential therapeutic target for mitigating cardiac hypertrophy.
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