TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation.

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Molecular Medicine

Background:

• Lysosomal dysfunction contributes to cardiomyocyte damage in myocardial infarction (MI).
• The role of lysosomal transmembrane protein 175 (TMEM175) in post-infarction cardiac dysfunction is not well understood.
• TMEM175 is crucial for maintaining lysosomal homeostasis.

Purpose of the Study:

• To investigate the role of TMEM175 in cardiac dysfunction following MI.
• To elucidate the molecular mechanisms by which TMEM175 influences lysosomal function and cardioprotection.

Main Methods:

• Utilized in vivo and in vitro gain- and loss-of-function models of TMEM175.
• Assessed cardiac injury markers, infarct size, and collagen deposition post-MI.
• Evaluated lysosomal function, including biogenesis, pH, enzyme activity, and autophagic flux.
• Investigated the impact of TMEM175 on mTORC1 phosphorylation and TFEB nuclear translocation under hypoxic stress.

Main Results:

• TMEM175 overexpression demonstrated significant cardioprotection in MI models, reducing infarct size and myocardial injury.
• Restored lysosomal function, normalized pH, enhanced enzyme activities, and improved autophagic flux were observed with TMEM175 overexpression.
• TMEM175 knockdown exacerbated cardiac pathologies and lysosomal dysfunction, particularly under hypoxic conditions.
• Mechanistically, MI-induced TMEM175 reduction led to increased mTORC1 phosphorylation and suppressed TFEB translocation, impairing lysosomal gene regulation.

Conclusions:

• TMEM175 plays a critical protective role in the post-MI heart by preserving lysosomal function and autophagy.
• Restoring TMEM175 levels can reverse MI-induced lysosomal dysfunction and ameliorate cardiac injury.
• TMEM175 deficiency exacerbates cardiac damage through mTORC1/TFEB pathway dysregulation.