TRPML1 Controls Mitochondrial Homeostasis and Alleviates Cardiac Hypertrophy by Inhibiting VDAC1 Oligomerization

Xiuye Zhao; Mingxiu Zhang; Changling Lv; Chunlei Duan; Zhen Chen; Yan Hao; Zhen Liang; Yiping Tao; Hongda Li; Zhenru Wang; Haonan Du; Jiapan Wang; Wenjie Liao; Peifeng Li; Jia Wang; Xueqi He; Yu Zhang; Xinyuan Hao; Hongyu Ji; Yan Zhang; Xingda Li; Ye Yuan; Zhimin Du

doi:10.1016/j.eng.2025.10.033

Engineering ›› :202510033 DOI: 10.1016/j.eng.2025.10.033

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TRPML1 Controls Mitochondrial Homeostasis and Alleviates Cardiac Hypertrophy by Inhibiting VDAC1 Oligomerization

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Abstract

The preservation of mitochondrial homeostasis plays a critical role in preventing the progression of pathological cardiac hypertrophy to heart failure (HF). Although transient receptor potential mucolipin 1 (TRPML1) has been recently linked to lysosomal homeostasis, its role in pressure overload-induced pathological cardiac hypertrophy remains unclear. Transcriptomic analyses of both mouse and human HF samples revealed the significant downregulation of TRPML1 expression. Cardiomyocyte-specific overexpression and pharmacological activation of TRPML1 markedly improved cardiac function, reduced mitochondrial oxidative stress, and increased energy production. In contrast, cardiomyocyte-specific deletion or pharmacological inhibition of TRPML1 exacerbated cardiac hypertrophy and mitochondrial dysfunction. Further investigations revealed that signal transducer and activator of transcription 5B (Stat5b) is a transcriptional regulator of TRPML1 in the context of cardiac hypertrophy. Mechanistically, the proteomic analysis revealed that the C-terminal domain of TRPML1 directly interacts with the N-terminal domain of voltage-dependent anion channel 1 (VDAC1). This interaction inhibited VDAC1 oligomerization, thereby maintaining mitochondrial calcium (Ca²⁺) homeostasis and the balance of mitochondrial fusion and fission in hypertrophic cardiomyocytes. The administration of 1,3-bis(4-aminophenyl)urea (NSC 15364) to inhibit VDAC1 oligomerization partially reversed cardiac hypertrophy in TRPML1 knockout mice. These findings highlight TRPML1 as a promising therapeutic target to suppress the progression of pathological cardiac hypertrophy to HF.

Keywords

Cardiac hypertrophy / Transient receptor potential mucolipin 1 / Voltage-dependent anion channel 1 / oligomerization / Lysosome / Mitochondria

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Xiuye Zhao, Mingxiu Zhang, Changling Lv, Chunlei Duan, Zhen Chen, Yan Hao, Zhen Liang, Yiping Tao, Hongda Li, Zhenru Wang, Haonan Du, Jiapan Wang, Wenjie Liao, Peifeng Li, Jia Wang, Xueqi He, Yu Zhang, Xinyuan Hao, Hongyu Ji, Yan Zhang, Xingda Li, Ye Yuan, Zhimin Du. TRPML1 Controls Mitochondrial Homeostasis and Alleviates Cardiac Hypertrophy by Inhibiting VDAC1 Oligomerization. Engineering 202510033 DOI:10.1016/j.eng.2025.10.033

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