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

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.