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PHB2 protects against pressure overload-induced myocardial remodeling in mice via stabilizing TOMM40 and regulating mitochondrial morphofunctional homeostasis

Acta Pharmacologica Sinica volume 46, pages 3217–3229 (2025)Cite this article

Abstract

Myocardial remodeling is critical pathological processes in various cardiovascular diseases, where redox imbalance and mitochondrial bioenergetic perturbations emerge as key determinants. Prohibitin 2 (PHB2), which resides in the mitochondrial inner membrane, serves as a critical regulator of mitochondrial homeostasis. In this study we investigated the protective role of PHB2 in transverse aortic constriction (TAC)-induced cardiac remodeling with a particular focus on its ability to safeguard the heart by improving mitochondrial function and alleviating oxidative stress. We revealed that PHB2 expression was significantly decreased in the heart of TAC mice and in Ang II (1 μM)-treated cardiomyocytes. Cardiac-specific PHB2 overexpression mitigated TAC-induced cardiac remodeling, improving cardiac function and attenuating hypertrophy. Additionally, PHB2 overexpression effectively suppressed oxidative stress in the hearts of TAC mice, while improving mitochondrial morphology and the integrity of inner membrane structure. Furthermore, PHB2 overexpression restored mitochondrial function in Ang II-treated cardiomyocytes evidenced by elevated ATP levels and enhanced oxidative phosphorylation capacity. IP-MS analysis revealed that PHB2 directly interacted with Transporter of Outer Mitochondrial Membrane 40 (TOMM40) to regulate mitochondrial function. Importantly, silencing TOMM40 abolished the protective effects of PHB2. We demonstrated that PHB2 preserves TOMM40 protein levels predominantly through inhibition of ubiquitin-dependent proteasomal degradation. Collectively, we discover a new function of PHB2 in safeguarding mitochondrial morphofunctional homeostasis in response to pathological stress through facilitating TOMM40 stabilization, suggesting PHB2 as a promising therapeutic target for potential interventions in heart diseases.

Schematic illustration of PHB2’s potential protective mechanism against cardiac hypertrophy. PHB2 protects against pressure overload-induced cardiac hypertrophy through preserving TOMM40 protein to maintain mitochondrial energetic homeostasis.

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Fig. 1: PHB2 expression is downregulated in both DCM and experimental hypertrophic models.
Fig. 2: Overexpression of PHB2 alleviated cardiomyocyte hypertrophy in vitro and cardiac remodeling in vivo.
Fig. 3: PHB2 silencing aggravated Ang II-induced cardiomyocyte hypertrophy in vitro.
Fig. 4: PHB2 overexpression alleviated oxidative stress in mouse hearts and in isolated cardiomyocytes.
Fig. 5: PHB2 overexpression improved mitochondrial morphology and function.
Fig. 6: PHB2 interacted with TOMM40 to regulate its expression level.
Fig. 7: PHB2 overexpression alleviated mitochondrial dysfunction through TOMM40 in isolated cardiomyocytes.
Fig. 8: PHB2 regulated TOMM40 expression by facilitating its stabilization.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China, including the Regional Innovation and Development Joint Fund (Grant No. U22A20269), the Key Program (Grant No. 81530012), and the Young Scientists Fund (Grant No. 82300270). Additional support was provided by the National Key R&D Program of China (Grant No. 2018YFC1311300).

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  1. These authors contributed equally: Dan Li, Jia-hao Li

Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Dan Li, Jia-hao Li, Ying-ying Guo, Ya-jie Chen, Meng Zhang, Fei-xue Xu, Wan-yi Li & Qi-zhu Tang

  2. Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China

    Dan Li, Jia-hao Li, Ying-ying Guo, Ya-jie Chen, Meng Zhang, Fei-xue Xu, Wan-yi Li & Qi-zhu Tang

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Contributions

DL, JHL and QZT designed research; DL, JHL, YYG, FXX, WYL performed the experiments; DL, YYG, YJC and MZ analyzed data; DL and JHL wrote the paper.

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Correspondence to Qi-zhu Tang.

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Li, D., Li, Jh., Guo, Yy. et al. PHB2 protects against pressure overload-induced myocardial remodeling in mice via stabilizing TOMM40 and regulating mitochondrial morphofunctional homeostasis. Acta Pharmacol Sin 46, 3217–3229 (2025). https://doi.org/10.1038/s41401-025-01613-8

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