ZEB1-AS1 as a TRPML1 Inhibitor to Cause Lysosome Dysfunction and Cardiac Damage in Aged Mice

Heng Liu; Haiying Zhang; Han Lou; Jennifer Wang; Shengxin Hao; Hui Chen; Chen Chen; Lei Wang; Huimin Li; Ziyu Meng; Wenjie Zhao; Tong Zhao; Yuan Lin; Zhimin Du; Xin Liu; Baofeng Yang; Yong Zhang

doi:10.1016/j.eng.2024.09.020

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Engineering ›› 2024, Vol. 43 ›› Issue (12) : 183-200. DOI: 10.1016/j.eng.2024.09.020

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Article

ZEB1-AS1 as a TRPML1 Inhibitor to Cause Lysosome Dysfunction and Cardiac Damage in Aged Mice

Heng Liu^a^,^b^,^# ,
Haiying Zhang^c^,^# ,
Han Lou^a^,^d^,^e^,^# ,
Jennifer Wang^f ,
Shengxin Hao^a^,^d^,^e ,
Hui Chen^a^,^d^,^e ,
Chen Chen^a^,^d^,^e ,
Lei Wang^a^,^d^,^e ,
Huimin Li^a^,^d^,^e ,
Ziyu Meng^a^,^d^,^e ,
Wenjie Zhao^a^,^d^,^e ,
Tong Zhao^a^,^d^,^e ,
Yuan Lin^a^,^d^,^e ,
Zhimin Du^g^,^h^,ⁱ ,
Xin Liu^a^,^d^,^e^,^* ,
Baofeng Yang^d^,^e^,^* ,
Yong Zhang^a^,^d^,^e^,^*

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Abstract

The prevalence of cardiovascular diseases (CVDs) has increased markedly as the world population has aged. Long non-coding RNAs (lncRNAs) have been reported as novel regulators in diverse pathophysiological conditions. Here, we performed RNA sequencing (RNA-seq) and observed that the lncRNA Zeb1os1 (zinc finger E-box binding homeobox 1, opposite strand 1), which is known as ZEB1-AS1 (zinc finger E-box binding homeobox 1 antisense 1) in humans, was upregulated in the aged mice hearts, senescent cardiomyocytes, and human blood from elderly individuals. The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A (E/A). Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice. On the other hand, Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice. Mechanistically, we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1 (TRPML1) for ubiquitination (UB)-mediated degradation. This process inhibits lysosomal Ca²⁺ efflux, impairing lysosome function. In addition, the functional domain of Zeb1os1, which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes. Together, these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.

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Keywords

Heart aging / Cardiomyocytes senescence / ZEB1-AS1 / TRPML1 / Lysosome

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Heng Liu, Haiying Zhang, Han Lou, Jennifer Wang, Shengxin Hao, Hui Chen, Chen Chen, Lei Wang, Huimin Li, Ziyu Meng, Wenjie Zhao, Tong Zhao, Yuan Lin, Zhimin Du, Xin Liu, Baofeng Yang, Yong Zhang. ZEB1-AS1 as a TRPML1 Inhibitor to Cause Lysosome Dysfunction and Cardiac Damage in Aged Mice. Engineering, 2024, 43(12): 183‒200 https://doi.org/10.1016/j.eng.2024.09.020

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