A study published in Engineering has identified a regulatory mechanism linking lysosomal function to mitochondrial stability in pathological cardiac hypertrophy, highlighting transient receptor potential mucolipin 1 (TRPML1) as a protective factor against the development of heart failure, according to a Jun. 16 report.
Researchers found that TRPML1 helps maintain mitochondrial homeostasis and alleviates 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 revealed consistent downregulation of TRPML1 expression, suggesting an association between reduced TRPML1 levels and pathological cardiac remodeling.
In animal models, overexpression or pharmacological activation of TRPML1 in cardiomyocytes preserved cardiac function, reduced mitochondrial oxidative stress, and increased energy production. In contrast, deletion or inhibition of TRPML1 worsened cardiac hypertrophy and mitochondrial dysfunction. Proteomic screening and molecular assays demonstrated that the C-terminal domain of TRPML1 binds directly to the N-terminal domain of VDAC1. This interaction suppresses VDAC1 oligomerization, helping preserve mitochondrial calcium balance and proper dynamics between fusion and fission in hypertrophic cardiomyocytes.
Treatment with NSC 15364, a small molecule inhibitor targeting VDAC1 oligomerization, partially reversed cardiac hypertrophy in mice lacking TRPML1. Further investigation identified signal transducer and activator of transcription 5B (Stat5b) as a transcriptional regulator for TRPML1 during cardiac hypertrophy; Stat5b normally enhances expression by binding to the promoter region under physiological conditions, but this regulation is impaired under stress.
The findings suggest that lysosomal TRPML1 acts as a guardian for mitochondrial integrity through its effect on VDAC1 oligomerization. Researchers propose that targeting this pathway could offer new directions for developing therapies aimed at slowing or preventing progression from pathological cardiac hypertrophy to heart failure.
