Lysosomal protein TRPML1 safeguards cardiac function by modulating mitochondrial homeostasis

A new study published in Engineering has uncovered a regulatory mechanism linking lysosomal function to mitochondrial stability in pathological cardiac hypertrophy, identifying transient receptor potential mucolipin 1 (TRPML1) as a key protective factor against the progression to heart failure. Researchers found that TRPML1 maintains mitochondrial homeostasis and relieves cardiac hypertrophy by directly inhibiting the oligomerization of voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane.

Transcriptomic analyses of heart failure samples from both mice and humans showed a consistent downregulation of TRPML1 expression, suggesting a potential association between reduced TRPML1 levels and pathological cardiac remodeling. In animal models, cardiomyocyte-specific overexpression or pharmacological activation of TRPML1 preserved cardiac function, lowered mitochondrial oxidative stress, and boosted energy production. Conversely, cardiomyocyte-specific deletion or pharmacological inhibition of TRPML1 worsened cardiac hypertrophy and mitochondrial dysfunction, supporting a protective role for this lysosomal ion channel.

Mechanistically, proteomic screening and molecular assays revealed that the C-terminal domain of TRPML1 binds directly to the N-terminal domain of VDAC1. This physical interaction suppresses VDAC1 oligomerization, which in turn preserves mitochondrial calcium homeostasis and the proper balance between mitochondrial fusion and fission in hypertrophic cardiomyocytes. Treatment with NSC 15364, a small molecule that inhibits VDAC1 oligomerization, partially reversed cardiac hypertrophy in TRPML1-deficient mice, confirming the functional importance of this interaction.

Further investigation identified signal transducer and activator of transcription 5B (Stat5b) as a transcriptional regulator of TRPML1 during cardiac hypertrophy. Under physiological conditions, Stat5b binds to the TRPML1 promoter and enhances its expression, while this regulatory axis is impaired under hypertrophic stress. The findings establish a novel interorganelle communication axis between lysosomes and mitochondria, where lysosomal TRPML1 acts as a guardian of mitochondrial integrity. By targeting VDAC1 oligomerization, TRPML1 could serve as a promising therapeutic candidate to slow the transition from pathological cardiac hypertrophy to heart failure, offering a new direction for the development of cardiovascular interventions.

The paper “TRPML1 Controls Mitochondrial Homeostasis and Alleviates Cardiac Hypertrophy by Inhibiting VDAC1 Oligomerization,” is authored by 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. Full text of the open access paper: https://doi.org/10.1016/j.eng.2025.10.033. For more information about Engineering, visit the website at https://www.sciencedirect.com/journal/engineering.