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YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases

Inna Rabinovich-Nikitin1, Lorrie A Kirshenbaum1,2

  • 1The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology and.

The Journal of Clinical Investigation
|March 1, 2021
PubMed

Insights

Lysosomal storage disorders (LSD) cause heart failure due to impaired cellular cleanup. The Yes-associated protein (YAP)/transcription factor EB (TFEB) pathway is crucial for clearing cellular waste, and its dysfunction leads to cardiac issues in LSD.

Area of Science:

  • Cardiovascular Biology
  • Cellular Biology
  • Genetics

Background:

  • Lysosomal storage disorders (LSD) are inherited metabolic diseases stemming from lysosomal enzyme deficiencies.
  • Cardiac involvement in LSD often manifests as cardiomyopathy, progressing to heart failure.
  • Cellular homeostasis is maintained by lysosome-dependent degradation, including autophagy, which removes damaged cellular components.

Purpose of the Study:

  • To investigate the signaling pathways regulating lysosomal proteins in the heart, particularly in the context of LSD.
  • To explore the role of transcription factor EB (TFEB) in cardiac LSD models.
  • To identify novel therapeutic targets for LSD-related cardiac dysfunction.

Main Methods:

  • Generation of a cardiac-specific mouse model for LSD.
  • Analysis of the Yes-associated protein (YAP)/TFEB signaling pathway.
  • Assessment of autophagosome clearance and cardiac function in the disease model.

Main Results:

  • Modulating TFEB alone was insufficient to fully restore lysosomal clearance in cardiac LSD.
  • The YAP/TFEB signaling pathway was identified as a critical regulator of autophagosome processing.
  • Accumulation of undigested autophagosomes was observed, correlating with cardiac cell death and dysfunction.

Conclusions:

  • The YAP/TFEB pathway plays a significant role in regulating autophagosome clearance in the heart.
  • Dysregulation of this pathway contributes to the cardiac pathology seen in LSD.
  • Targeting the YAP/TFEB pathway may offer a therapeutic strategy for LSD-related cardiomyopathy.

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