Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression

• Published in: Cell death and differentiation Vol. 24; no. 6; pp. 1111 - 1120
• Main Authors: Wang, Kun, Gan, Tian-Yi, Li, Na, Liu, Cui-Yun, Zhou, Lu-Yu, Gao, Jin-Ning, Chen, Chao, Yan, Kao-Wen, Ponnusamy, Murugavel, Zhang, Yu-Hui, Li, Pei-Feng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2017; Nature Publishing Group
• Subjects: 13/109; 13/2; 13/51; 13/89; 13/95; 38; 38/44; 38/90; 631/337; 692/699/75; Animals; Apoptosis; Biochemistry; Biomarkers; Biomedical and Life Sciences; Cancer; Cardiomyocytes; Cardiovascular disease; Cell Biology; Cell Cycle Analysis; Cell death; Gene Expression Regulation; Heart; Heart failure; Life Sciences; Medicine; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; MicroRNAs; MicroRNAs - metabolism; Mitochondria; Mitochondria - metabolism; Mitochondria - physiology; Mitochondrial Dynamics; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Original Paper; RNA - metabolism; Signal Transduction; Stem Cells; Tumor Suppressor Proteins - metabolism; Up-Regulation; Beijing China; China
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2017.61

Circular RNAs (circRNAs) have important roles in several cellular processes. No study has established the pathophysiological role for circRNAs in the heart. Here, we show that a circRNA (mitochondrial fission and apoptosis-related circRNA (MFACR)) regulates mitochondrial fission and apoptosis in the heart by directly targeting and downregulating miR-652-3p; this in turn blocks mitochondrial fission and cardiomyocyte cell death by suppressing MTP18 translation. MTP18 deficiency reduces mitochondrial fission and suppresses cardiomyocyte apoptosis and MI. miR-652-3p directly downregulates MTP18 and attenuates mitochondrial fission, cardiomyocyte apoptosis, and MI in vitro and in vivo . MFACR directly sequesters miR-652-3p in the cytoplasm and inhibits its activity. MFACR knockdown in cardiomyocytes and mice attenuates mitochondrial fission and MI. Our results reveal a crucial role for circRNA in regulating mitochondrial dynamics and apoptosis in the heart; as such, circRNAs may serve as a potential therapeutic avenue for cardiovascular diseases.