PT  - JOURNAL ARTICLE
AU  - Bin Lu
AU  - Fugen Shangguan
AU  - Dawei Huang
AU  - Shiwei Gong
AU  - Yingchao Shi
AU  - Zhiying Song
AU  - Lianqun Jia
AU  - Juan Xu
AU  - Chaojun Yan
AU  - Tongke Chen
AU  - Mingjie Xu
AU  - Yujie Li
AU  - Shengnan Han
AU  - Nan Song
AU  - Pingyi Chen
AU  - Lu Wang
AU  - Yongzhang Liu
AU  - Xingxu Huang
AU  - Carolyn K. Suzuki
AU  - Zhongzhou Yang
AU  - Guanlin Yang
TI  - LonP1 Orchestrates UPR<sup>mt</sup> and UPR<sup>ER</sup> and Mitochondrial Dynamics to Regulate Heart Function
AID  - 10.1101/564492
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 564492
4099  - http://biorxiv.org/content/early/2019/03/01/564492.short
4100  - http://biorxiv.org/content/early/2019/03/01/564492.full
AB  - Protein quality control is pivotal to cellular homeostasis and integrity of cardiomyocytes for maintenance of normal heart function. The unfolded protein response (UPR) is an adaptive process to modulate protein quality control in the endoplasmic reticulum (ER) and mitochondria, and is accordingly termed UPRER and UPRmt, respectively. Lon protease (LonP1) is a highly conserved mitochondrial protease to modulate UPRmt, which is involved in regulating metabolism, mitophagy, and stress response. However, whether LonP1 regulates UPRER remains elusive. To investigate the regulation of protein quality control in cardiomyocytes, we generated cardiac-specific LonP1 deletion mice. Our findings show that LonP1 deficiency caused impaired mitochondrial respiratory function and fragmentation. Surprisingly, both UPRER and UPRmt is substantially induced in LonP1-deletion heart suggesting of LonP1 as a novel regulator of UPRER; however, the activation of UPRER occurs earlier than UPRmt in response to LonP1 deletion. Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming of cardiomyocytes, pathological heart remodeling, as well as impeded heart function. Thus, we uncovered the novel function of LonP1 as an UPRmt mediator, and reciprocal orchestration of UPRmt and UPRER and mitochondrial dynamics regulated by LonP1 in the cardiomyocytes that is critical to maintain heart function, which offers exciting new insights into the potential therapeutic strategy for heart failure.