Targeting Lysosomal MCOLN1/TRPML1 Ion Channels to Alleviate Diabetes Mellitus via a Ca2+- CaMKKβ-AMPK pathway
- 1Zhejiang University of Technology
Abstract
Type 2 Diabetes mellitus (T2DM) is a metabolic syndrome characterized by hyperglycemia and various complications. Current drugs are limited by side effects and resistance, necessitating novel targets and therapies. Previous studies have shown that MK-83, a synthetic agonist of transient receptor potential mucolipin 1 (TRPML1/ MCOLN1), a lysosomal Ca2+ channel, activates adenosine 5'-monophosphate-activated protein kinase (AMPK), a key therapeutic target in diabetes. However, whether targeting TRPML1 can treat T2DM remains unclear. In this study, we found that transgenic overexpression or pharmacological activation of TRPML1 regulates AMPK phosphorylation via a Ca2+-CaMKK{beta}-dependent mechanism. This activation promotes glucose transporter 4 (GLUT4) translocation and increases intracellular glucose uptake. Conversely, genetic inactivation or pharmacologically inhibition of TRPML1 blocks both AMPK activation and glucose uptake. More importantly, pharmacological activation of TRPML1 in vivo alleviates hyperglycemia in db/db mice (a T2DM model), as evidenced by random blood glucose levels, fasting blood glucose levels and HbA1c levels. Furthermore, other hallmark features of db/db mice- including impaired oral glucose tolerance, reduced insulin tolerance, and elevated ALT and AST levels- were all ameliorated upon TRPML1 activation. Hence, targeting lysosomal TRPML1 channel represents a promising therapeutic strategy for T2DM, with highly specific TRPML1 agonists as potential anti-diabetic agents.
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BibTeX
@misc{zhu2026targeting,
title = {{Targeting Lysosomal MCOLN1/TRPML1 Ion Channels to Alleviate Diabetes Mellitus via a Ca2+- CaMKKβ-AMPK pathway}},
author = {J. Zhu and Z. Pan and S. Wang and H. Zhang and Q. Wang and Z. Jiang and Y. Wang and Z. Ding and D. Li},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.16.732532},
url = {https://www.biorxiv.org/content/10.64898/2026.06.16.732532v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Targeting Lysosomal MCOLN1/TRPML1 Ion Channels to Alleviate Diabetes Mellitus via a Ca2+- CaMKKβ-AMPK pathway
AU - J. Zhu
AU - Z. Pan
AU - S. Wang
AU - H. Zhang
AU - Q. Wang
AU - Z. Jiang
AU - Y. Wang
AU - Z. Ding
AU - D. Li
PY - 2026
DA - 2026/06/16
PB - bioRxiv
DO - 10.64898/2026.06.16.732532
UR - https://www.biorxiv.org/content/10.64898/2026.06.16.732532v2
AB - Type 2 Diabetes mellitus (T2DM) is a metabolic syndrome characterized by hyperglycemia and various complications. Current drugs are limited by side effects and resistance, necessitating novel targets and therapies. Previous studies have shown that MK-83, a synthetic agonist of transient receptor potential mucolipin 1 (TRPML1/ MCOLN1), a lysosomal Ca2+ channel, activates adenosine 5'-monophosphate-activated protein kinase (AMPK), a key therapeutic target in diabetes. However, whether targeting TRPML1 can treat T2DM remains unclear. In this study, we found that transgenic overexpression or pharmacological activation of TRPML1 regulates AMPK phosphorylation via a Ca2+-CaMKK{beta}-dependent mechanism. This activation promotes glucose transporter 4 (GLUT4) translocation and increases intracellular glucose uptake. Conversely, genetic inactivation or pharmacologically inhibition of TRPML1 blocks both AMPK activation and glucose uptake. More importantly, pharmacological activation of TRPML1 in vivo alleviates hyperglycemia in db/db mice (a T2DM model), as evidenced by random blood glucose levels, fasting blood glucose levels and HbA1c levels. Furthermore, other hallmark features of db/db mice- including impaired oral glucose tolerance, reduced insulin tolerance, and elevated ALT and AST levels- were all ameliorated upon TRPML1 activation. Hence, targeting lysosomal TRPML1 channel represents a promising therapeutic strategy for T2DM, with highly specific TRPML1 agonists as potential anti-diabetic agents.
ER -