Mitochondrial calcium uniporter inhibition provides cardioprotection in pressure overload-induced heart failure through autophagy enhancement.
BACKGROUND
HF incurs high disease burden, and the effectiveness of known HF treatments is unsatisfactory. Therefore, seeking novel therapeutic target of HF is important. The present study aimed to investigate the role of the mitochondrial calcium uniporter (MCU) and its relationship with autophagy in overload-induced heart failure (HF).


METHODS AND RESULTS
In both early-stage and end-stage of pressure overload-induced HF, MCU appeared up-regulated along with heart enlargement, increased microtubule-associated proteins 1A/1B light chain 3B (LC3B) II/I ratio and autophagosome content, damaged cardiac function, and ventricular asynchrony. However, sequestosome-1 (SQSTM1/p62) level decreased indicating blockaded autophagic flux. Seven-week administration of MCU inhibitor ruthenium red improved cardiac function and mitigated its pathological change. MCU inhibition maintained mitochondrial integrity, increased LC3B II/I ratio, up-regulated Parkin and Pink1, and down-regulated SQSTM1/p62. MCU inhibition also alleviated ventricular asynchrony of HF, and this might be related to connexin-43 up-regulation. In vitro study validated intervention on MCU leading to elevation of autophagy and mitophagy. MCU inhibition could partly prevent from excessive cellular enlargement induced by isoprenaline.


CONCLUSIONS
In summary, MCU inhibition played an important role in pressure overload-induced heart failure through autophagy and mitophagy enhancement, and intervention on MCU offered cardioprotective effects. To our knowledge, the role of MCU in HF and its relationship with autophagy and mitophagy are firstly disclosed. Moreover, our study suggests that MCU inhibition could be explored as a novel therapeutic concept in HF.
['Yu|Ziqing|Z|', 'Chen|Ruizhen|R|', 'Li|Minghui|M|', 'Yu|Yong|Y|', 'Liang|Yixiu|Y|', 'Han|Fei|F|', 'Qin|Shengmei|S|', 'Chen|Xueying|X|', 'Su|Yangang|Y|', 'Ge|Junbo|J|']
D000818:Animals D001343:Autophagy D015220:Calcium Channels D002478:Cells, Cultured D006333:Heart Failure D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008929:Mitochondria, Heart D012430:Ruthenium Red D015854:Up-Regulation
Mitochondrial calcium uniporter Heart failure Autophagy Ventricular asynchrony Transverse aortic constriction