A study published in Engineering has identified transient receptor potential mucolipin 1 (TRPML1), a lysosomal ion channel, as a protective factor against the progression of pathological cardiac hypertrophy to heart failure, establishing a previously unrecognised communication pathway between lysosomes and mitochondria in cardiomyocytes.
Transcriptomic analysis of heart failure samples from both mice and humans showed consistent downregulation of TRPML1 expression, suggesting an association between reduced TRPML1 levels and pathological cardiac remodelling. In animal models, cardiomyocyte-specific overexpression or pharmacological activation of TRPML1 preserved cardiac function, reduced mitochondrial oxidative stress, and improved energy production. Conversely, cardiomyocyte-specific deletion or pharmacological inhibition of TRPML1 worsened both cardiac hypertrophy and mitochondrial dysfunction, supporting a protective role for the channel.
Mechanistically, proteomic screening and molecular assays demonstrated that the C-terminal domain of TRPML1 binds directly to the N-terminal domain of voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane. This interaction suppresses VDAC1 oligomerisation, thereby preserving mitochondrial calcium homeostasis and maintaining an appropriate balance between mitochondrial fusion and fission in hypertrophic cardiomyocytes. Treatment with NSC 15364, a small molecule that inhibits VDAC1 oligomerisation, partially reversed cardiac hypertrophy in TRPML1-deficient mice, confirming the functional relevance of this pathway.
Further analysis identified signal transducer and activator of transcription 5B (Stat5b) as a transcriptional regulator of TRPML1. Under physiological conditions, Stat5b binds to the TRPML1 promoter to enhance its expression, but this regulatory mechanism is impaired under hypertrophic stress.
The authors propose that targeting VDAC1 oligomerisation via the TRPML1 pathway may represent a novel therapeutic strategy for slowing the transition from cardiac hypertrophy to heart failure.
Source: Zhao X et al. TRPML1 Controls Mitochondrial Homeostasis and Alleviates Cardiac Hypertrophy by Inhibiting VDAC1 Oligomerization. Engineering (2025). DOI: 10.1016/j.eng.2025.10.033
