Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy

Lei Wang1, Xue-qing Tang1, Yang Shi1, Hui-min Li1, Zi-yu Meng1, Hui Chen1, Xiao-han Li1, Yong-chao Chen1, Heng Liu1, Yang Hong1, Heng-hui Xu1, Ling Liu1, Limin Zhao1, Wei-na Han2, Xin Liu1,3, Yong Zhang1,3,4
1 Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
2 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China
3 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin 150081, China
4 Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin 150081, China
Correspondence to: Xin Liu:, Yong Zhang:,
DOI: 10.1038/s41401-022-00956-w
Received: 31 January 2022
Accepted: 7 July 2022
Advance online: 10 August 2022


Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg−1 · d−1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg−1 · d−1) or THBru (25, 50 mg · kg−1 · d−1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 μM) and THBru (20, 40 μM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.

Keywords: heart aging; berberine; tetrahydroberberrubine; mitophagy; PHB2; antiaging medicine

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