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Published on: June 3, 2018
TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation
Chen Chen1,2,3, Han Lou1,2,3, An-Ge Hu1,2,3
1State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy; and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China.
Abstract:
Lysosomal dysfunction exacerbates cardiomyocyte damage in myocardial infarction (MI) by impairing cellular degradation. However, the precise molecular mechanisms driving this pathologic process remain unclear. Lysosomal transmembrane protein 175 (TMEM175) is critical for regulating lysosomal homeostasis. But its pathophysiological implications in post-infarction cardiac dysfunction are not fully understood. By using both gain and loss of function approaches in vivo and in vitro, we discovered that TMEM175 overexpression conferred cardioprotection in MI models. This was evidenced by reduced infarct size, collagen deposition, and myocardial injury, accompanied by restored lysosomal function characterized by increased biogenesis, normalized pH, enzyme activities, and autophagic flux. Conversely, TMEM175 knockdown exacerbated these pathologies. Under hypoxic stress, TMEM175 overexpression in neonatal mouse cardiomyocytes (NMCMs) improved cell viability and corrected lysosomal dysfunction, whereas its knockdown worsened the aforementioned effects. Mechanistically, the reduction of TMEM175 induced by MI increases mammalian target of rapamycin complex 1 (mTORC1) phosphorylation on lysosomal membranes and suppresses the nuclear translocation of transcription factor EB (TFEB), thereby impairing TFEB's transcriptional regulation of lysosome-associated genes. Meanwhile, TMEM175 restoration reversing this cascade, and restoring lysosomal function and autophagic flux.
Insights
Lysosomal transmembrane protein 175 (TMEM175) protects the heart after myocardial infarction (MI) by restoring lysosomal function and improving cellular degradation. TMEM175 deficiency worsens cardiac injury and impairs autophagy.
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.
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