MiR-485-5p modulates mitochondrial fission through targeting mitochondrial anchored protein ligase in cardiac hypertrophy

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.

Haemin pre‐treatment augments the cardiac protection of mesenchymal stem cells by inhibiting mitochondrial fission and improving survival

“…However, this balance is disrupted under stress conditions, resulting in apoptosis. 31 In the current study, we found that the mi- injury. Furthermore, these protective effects were partially reversed by ZnPP, a haemin inhibitor.…”

miR‐376b‐3p attenuates mitochondrial fission and cardiac hypertrophy by targeting mitochondrial fission factor

“…Thus, it provides new evidences to explore the functions of miRNAs in modulating mitochondrial function. For instance, miR‐106a accelerates cardiac hypertrophy via restraining mitofusin 2, miR‐497 and miR‐485‐5p attenuate cardiac hypertrophy by targeting Sirt4 and MAPL, respectively . In present study, we found that miRNA‐miR‐376b‐3p negatively regulate mitochondrial fission in cardiac hypertrophic NRVCs by targeting MFF.…”

“…For instance, miR-106a accelerates cardiac hypertrophy via restraining mitofusin 2, 30 miR-497 and miR-485-5p attenuate cardiac hypertrophy by targeting Sirt4 and MAPL, respectively. 26,31 In present study, we found that miRNA-miR-376b-3p negatively regulate mitochondrial fission in cardiac hypertrophic NRVCs by targeting MFF. miR-376b plays major roles in regulating of various biology activities including cancer, 32,33 liver regeneration, 34 angiogenesis 35 and cardioprotection.…”

Mitochondrial MiRNA in Cardiovascular Function and Disease

“…In addition, miR-30 has been reported to antagonize apoptosis of cardiac cells through negatively regulating Drp1, an initiator of mitochondrial fission, Bcl-2, and Bnip3L/Nix, leading to apoptosis [55,68]. MiR-485-5p directly downregulated mitochondrial anchored protein ligase, an important contributor in the mitochondrial fission process, and upregulated mitochondrial fusion protein 2 (Mfn2) in primary hypertrophic cardiomyocytes [69]. In vivo, miR-485-5p agomir suppressed cardiac hypertrophy in mice [69].…”

“…MiR-485-5p directly downregulated mitochondrial anchored protein ligase, an important contributor in the mitochondrial fission process, and upregulated mitochondrial fusion protein 2 (Mfn2) in primary hypertrophic cardiomyocytes [69]. In vivo, miR-485-5p agomir suppressed cardiac hypertrophy in mice [69]. Thus, mitomiRs may be potential markers in cardiac hypertrophy and may negatively or positively regulate the progression of pathological cardiac remodeling through modulation of mitochondrial fusion-fission and function.…”