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

Acta Pharmacologica Sinica (2026)Cite this article

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.

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Fig. 1: TMEM175 is downregulated in MI hearts.
Fig. 2: TMEM175 overexpression enhances cardiac function in MI mice.
Fig. 3: Downregulation of TMEM175 aggravates myocardial cell damage in MI.
Fig. 4: TMEM175 alleviated lysosomal damage and enhanced energy metabolism in mice with MI.
Fig. 5: Overexpression of TMEM175 improves lysosomal function in response to hypoxia.
Fig. 6: Overexpression of TMEM175 promotes autophagy by regulating the mTORC1/TFEB signaling pathway.
Fig. 7: Rapamycin rescues TMEM175 deficiency-induced lysosomal and autophagic dysfunction via the mTORC1/TFEB pathway.

References

  1. Tibaut M, Mekis D, Petrovic D. Pathophysiology of myocardial infarction and acute management strategies. Cardiovasc Hematol Agents Med Chem. 2017;14:150–9.

    Article  PubMed  Google Scholar 

  2. Yap J, Irei J, Lozano-Gerona J, Vanapruks S, Bishop T, Boisvert WA. Macrophages in cardiac remodelling after myocardial infarction. Nat Rev Cardiol. 2023;20:373–85.

    Article  PubMed  Google Scholar 

  3. Tai G, Liu R, Lin T, Yang J, Li X, Xu M. Intervention of natural products targeting novel mechanisms after myocardial infarction. Chin J Nat Med. 2025;23:658–72.

    CAS  PubMed  Google Scholar 

  4. Yu P, Song S, Zhang X, Cui S, Wei G, Huang Z, et al. Downregulation of apoptotic repressor AVEN exacerbates cardiac injury after myocardial infarction. Proc Natl Acad Sci USA. 2023;120:e2302482120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tan JX, Finkel T. A phosphoinositide signalling pathway mediates rapid lysosomal repair. Nature. 2022;609:815–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Manivannan MS, Peters A, Gibson SB. Lysosome targeted therapies in hematological malignancies. Front Oncol. 2025;15:1549792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang C, Wang X. Lysosome biogenesis: regulation and functions. J Cell Biol. 2021;220:e202102001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2020;21:101–18.

    Article  CAS  PubMed  Google Scholar 

  9. Bhat OM, Li PL. Lysosome function in cardiovascular diseases. Cell Physiol Biochem. 2021;55:277–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chi C, Riching AS, Song K. Lysosomal abnormalities in cardiovascular disease. Int J Mol Sci. 2020;21:811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hu M, Li P, Wang C, Feng X, Geng Q, Chen W, et al. Parkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes. Cell. 2022;185:2292–308. e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jing CC, Luo XG, Cui HG, Li FR, Li P, Jiang EZ, et al. Screening of polymorphisms located in the FGF20 and TMEM175 genes in North Chinese Parkinson’s disease patients. Genet Mol Res. 2015;14:13679–87.

    Article  CAS  PubMed  Google Scholar 

  13. Jinn S, Blauwendraat C, Toolan D, Gretzula CA, Drolet RE, Smith S, et al. Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease. Hum Mol Genet. 2019;28:3244–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wie J, Liu Z, Song H, Tropea TF, Yang L, Wang H, et al. Author correction: a growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology. Nature. 2021;592:E10.

    Article  CAS  PubMed  Google Scholar 

  15. Cang C, Aranda K, Seo YJ, Gasnier B, Ren D. TMEM175 is an organelle K+ channel regulating lysosomal function. Cell. 2015;162:1101–12.

    Article  CAS  PubMed  Google Scholar 

  16. Carroll B, Dunlop EA. The lysosome: a crucial hub for AMPK and mTORC1 signalling. Biochem J. 2017;474:1453–66.

    Article  CAS  PubMed  Google Scholar 

  17. Kim YM, Jung CH, Seo M, Kim EK, Park JM, Bae SS, et al. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol Cell. 2015;57:207–18.

    Article  CAS  PubMed  Google Scholar 

  18. Rabanal-Ruiz Y, Otten EG, Korolchuk VI. mTORC1 as the main gateway to autophagy. Essays Biochem. 2017;61:565–84.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sciarretta S, Forte M, Frati G, Sadoshima J. New insights into the role of mTOR signaling in the cardiovascular system. Circ Res. 2018;122:489–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Napolitano G, Di Malta C, Esposito A, de Araujo MEG, Pece S, Bertalot G, et al. A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. Nature. 2020;585:597–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yu W, Sun S, Xu H, Li C, Ren J, Zhang Y. TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury. Theranostics. 2020;10:11244–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ritzel RM, Li Y, Jiao Y, Lei Z, Doran SJ, He J, et al. Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration. Sci Adv. 2023;9:eadd1101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu J, Yang KC, Go NE, Colborne S, Ho CJ, Hosseini-Beheshti E, et al. Chloroquine treatment induces secretion of autophagy-related proteins and inclusion of Atg8-family proteins in distinct extracellular vesicle populations. Autophagy. 2022;18:2547–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhou J, Tan SH, Nicolas V, Bauvy C, Yang ND, Zhang J, et al. Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion. Cell Res. 2013;23:508–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, et al. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. Proc Natl Acad Sci USA. 2017;114:2389–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wie J, Liu Z, Song H, Tropea TF, Yang L, Wang H, et al. A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology. Nature. 2021;591:431–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen F, Tang H, Li C, Kang R, Tang D, Liu J. CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer. Nat Commun. 2025;16:2278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen S, Wang K, Fan Z, Zhou T, Li R, Zhang B, et al. Modulation of anti-cardiac fibrosis immune responses by changing M2 macrophages into M1 macrophages. Mol Med. 2024;30:88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee SH, Jang JS, Mo S, Kim HH. TMEM175 plays a crucial role in osteoblast differentiation by regulating lysosomal function and autophagy. Mol Cells. 2024;47:100127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu N, Fan X, Shao Y, Chen S, Wang T, Yao T, et al. Resveratrol attenuates inflammation and fibrosis in rheumatoid arthritis-associated interstitial lung disease via the AKT/TMEM175 pathway. J Transl Med. 2024;22:457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang X, Wu R, Zhai P, Liu Z, Xia R, Zhang Z, et al. Hypoxia promotes EV secretion by impairing lysosomal homeostasis in HNSCC through negative regulation of ATP6V1A by HIF-1α. J Extracell Vesicles. 2023;12:e12310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang H, Tian Y, Yu W, Tong D, Ji Y, Qu X, et al. TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic-ischemic brain injury. J Cell Physiol. 2023;238:2512–27.

    Article  CAS  PubMed  Google Scholar 

  33. Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021;101:1371–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Völkers M, Konstandin MH, Doroudgar S, Toko H, Quijada P, Din S, et al. Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation. 2013;128:2132–44.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Stähli BE, Klingenberg R, Heg D, Branca M, Manka R, Kapos I, et al. Mammalian target of rapamycin inhibition in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2022;80:1802–14.

    Article  PubMed  Google Scholar 

  36. Zhang Z, Fan Q, Luo X, Lou K, Weiss WA, Shokat KM. Brain-restricted mTOR inhibition with binary pharmacology. Nature. 2022;609:822–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Buss SJ, Muenz S, Riffel JH, Malekar P, Hagenmueller M, Weiss CS, et al. Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol. 2009;54:2435–46.

    Article  CAS  PubMed  Google Scholar 

  38. Takikawa H, Narita T, Sano N, Yamanaka M. Glucuronidation of bile acids by their high-dose infusion into rats. Hepatology. 1991;13:1222–8.

    CAS  PubMed  Google Scholar 

  39. Zhang D, Contu R, Latronico MV, Zhang J, Rizzi R, Catalucci D, et al. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest. 2010;120:2805–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sun CY, Li YZ, Cao D, Zhou YF, Zhang MY, Wang HY. Rapamycin and trametinib: a rational combination for treatment of NSCLC. Int J Biol. Sci. 2021;17:3211–23.

  41. Flynn JM, O’Leary MN, Zambataro CA, Academia EC, Presley MP, Garrett BJ, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013;12:851–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dai DF, Karunadharma PP, Chiao YA, Basisty N, Crispin D, Hsieh EJ, et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell. 2014;13:529–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012;8:903–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang W, Xia Z, Farré JC, Subramani S. TRIM37 deficiency induces autophagy through deregulating the MTORC1-TFEB axis. Autophagy. 2018;14:1574–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science. 2011;334:678–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999;340:1801–11.

    Article  CAS  PubMed  Google Scholar 

  47. Li SH, Graham BM. Why are women so vulnerable to anxiety, trauma-related and stress-related disorders? The potential role of sex hormones. Lancet Psychiatry. 2017;4:73–82.

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0537908), and the National Natural Science Foundation of China (82273919, 82270396, U24A20813 and 82570453).

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  1. These authors contributed equally: Chen Chen, Han Lou

Authors and Affiliations

  1. State 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

    Chen Chen, Han Lou, An-ge Hu, Qiang Huang, Ling-yi Kong, Zhou-xiu Chen, Heng-hui Xu, Yong-chao Chen, Heng Liu, Shu-qin Duan, Yuan Lin, Li-min Zhao, Ling Liu, Muneer Ahmed Khoso, Xin Liu & Yong Zhang

  2. State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150001, China

    Chen Chen, Han Lou, An-ge Hu, Qiang Huang, Ling-yi Kong, Zhou-xiu Chen, Heng-hui Xu, Yong-chao Chen, Heng Liu, Shu-qin Duan, Yuan Lin, Li-min Zhao, Ling Liu, Muneer Ahmed Khoso, Xin Liu & Yong Zhang

  3. Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150001, China

    Chen Chen, Han Lou, An-ge Hu, Qiang Huang, Ling-yi Kong, Zhou-xiu Chen, Heng-hui Xu, Yong-chao Chen, Heng Liu, Shu-qin Duan, Yuan Lin, Li-min Zhao, Ling Liu, Muneer Ahmed Khoso, Xin Liu & Yong Zhang

  4. School of Pharmacy, Jining Medical University, Rizhao, 276800, China

    Li-min Zhao

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Contributions

YZ, XL, CC, and HL conceived and designed the research and supervised the studies; CC, HL, AGH, and QH performed the experiment; LYK, ZXC, HHX, YCC, and HL participated in the in vivo and in vitro experiment; YL, LMZ, SQD, MAK, and LL conducted analyses; YZ, XL, CC, and HL contributed to drafting the manuscript and revising for important intellectual content. All authors read and approved the final manuscript.

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Correspondence to Xin Liu or Yong Zhang.

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Chen, C., Lou, H., Hu, Ag. et al. TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01749-1

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