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Peer-reviewedCC BYClinical and translational medicine

Lysosomal protein transmembrane 5 protects against myocardial ischemia-reperfusion injury by promoting mitophagy via the NEDD4-LC3 axis.

  • Yadan Zhang1,2,3,4
  • Qingqing Wu5
  • Yang Xiao1,2,3,4
  • Ying Liu1,2,3
  • Qi Yao1,2,3
  • Jiabin Yu1,2,3
  • Shasha Wang2
  • Si Chen2
  • Xiaofeng Zeng2
  • Qizhu Tang1,2,3,4
5 affiliations
  1. 1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P. R. China.
  2. 2Cardiovascular Research Institute of Wuhan University, Wuhan, P. R. China.
  3. 3Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, P. R. China.
  4. 4Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China.
  5. 5Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, China.
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Abstract

Background

Mitophagy is essential for mitochondrial quality control during myocardial ischemia-reperfusion (I/R) injury. Lysosomal protein transmembrane 5 (LAPTM5) has been implicated in cardiovascular disease and autophagy, but its role in cardiac mitophagy remains unclear.Methods

LAPTM5 knockout mice and cardiomyocyte-targeted AAV9-cTnT-LAPTM5 were used to determine the role of LAPTM5 in myocardial I/R injury. Cardiomyocyte hypoxia/reoxygenation models, mt-Keima imaging, mitochondrial fractionation, LC3-mitochondrial colocalization, co-immunoprecipitation, molecular docking, site-directed mutagenesis, NEDD4 gain- and loss-of-function, and p62 ubiquitination assays were used to investigate the underlying mechanism. Depending on data distribution and group number, appropriate parametric or non-parametric statistics were applied together with correction for multiple testing.Results

LAPTM5 expression progressively decreased following I/R or H/R stress. LAPTM5 deficiency aggravated myocardial injury, cardiac dysfunction, and mitochondrial structural and functional damage, whereas LAPTM5 overexpression attenuated these abnormalities. LAPTM5 promoted mitophagy by enhancing LC3 recruitment to mitochondria. Mechanistically, LAPTM5 recruited NEDD4 to mitochondria through its PY3 motif and facilitated NEDD4-LC3 complex formation. NEDD4 depletion abolished LAPTM5-mediated mitophagy and cytoprotection, whereas re-expression of NEDD4-WT, but not the E3-inactive NEDD4-CS mutant, restored these effects. NEDD4-WT also increased p62 ubiquitination. AAV9-mediated LAPTM5 re-expression reduced infarct size, improved cardiac function, and preserved mitochondrial integrity in LAPTM5-deficient hearts.Conclusions

LAPTM5 protects against myocardial I/R injury by promoting mitophagy through the NEDD4-LC3 axis. PY3-dependent recruitment of NEDD4 and its E3 ubiquitin ligase activity facilitate LC3-associated mitochondrial clearance, accompanied by enhanced p62 ubiquitination, thereby preserving mitochondrial homeostasis during reperfusion.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026lysosomal,
  title = {{Lysosomal protein transmembrane 5 protects against myocardial ischemia-reperfusion injury by promoting mitophagy via the NEDD4-LC3 axis.}},
  author = {Yadan Zhang and Qingqing Wu and Yang Xiao and Ying Liu and Qi Yao and Jiabin Yu and Shasha Wang and Si Chen and Xiaofeng Zeng and Qizhu Tang},
  journal = {Clinical and translational medicine},
  year = {2026},
  month = oct,
  doi = {10.1002/ctm2.70876},
  url = {https://europepmc.org/article/MED/42908113},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Lysosomal protein transmembrane 5 protects against myocardial ischemia-reperfusion injury by promoting mitophagy via the NEDD4-LC3 axis.
AU  - Yadan Zhang
AU  - Qingqing Wu
AU  - Yang Xiao
AU  - Ying Liu
AU  - Qi Yao
AU  - Jiabin Yu
AU  - Shasha Wang
AU  - Si Chen
AU  - Xiaofeng Zeng
AU  - Qizhu Tang
PY  - 2026
DA  - 2026/10/01
JO  - Clinical and translational medicine
DO  - 10.1002/ctm2.70876
UR  - https://europepmc.org/article/MED/42908113
AB  - Background  Mitophagy is essential for mitochondrial quality control during myocardial ischemia-reperfusion (I/R) injury. Lysosomal protein transmembrane 5 (LAPTM5) has been implicated in cardiovascular disease and autophagy, but its role in cardiac mitophagy remains unclear.Methods  LAPTM5 knockout mice and cardiomyocyte-targeted AAV9-cTnT-LAPTM5 were used to determine the role of LAPTM5 in myocardial I/R injury. Cardiomyocyte hypoxia/reoxygenation models, mt-Keima imaging, mitochondrial fractionation, LC3-mitochondrial colocalization, co-immunoprecipitation, molecular docking, site-directed mutagenesis, NEDD4 gain- and loss-of-function, and p62 ubiquitination assays were used to investigate the underlying mechanism. Depending on data distribution and group number, appropriate parametric or non-parametric statistics were applied together with correction for multiple testing.Results  LAPTM5 expression progressively decreased following I/R or H/R stress. LAPTM5 deficiency aggravated myocardial injury, cardiac dysfunction, and mitochondrial structural and functional damage, whereas LAPTM5 overexpression attenuated these abnormalities. LAPTM5 promoted mitophagy by enhancing LC3 recruitment to mitochondria. Mechanistically, LAPTM5 recruited NEDD4 to mitochondria through its PY3 motif and facilitated NEDD4-LC3 complex formation. NEDD4 depletion abolished LAPTM5-mediated mitophagy and cytoprotection, whereas re-expression of NEDD4-WT, but not the E3-inactive NEDD4-CS mutant, restored these effects. NEDD4-WT also increased p62 ubiquitination. AAV9-mediated LAPTM5 re-expression reduced infarct size, improved cardiac function, and preserved mitochondrial integrity in LAPTM5-deficient hearts.Conclusions  LAPTM5 protects against myocardial I/R injury by promoting mitophagy through the NEDD4-LC3 axis. PY3-dependent recruitment of NEDD4 and its E3 ubiquitin ligase activity facilitate LC3-associated mitochondrial clearance, accompanied by enhanced p62 ubiquitination, thereby preserving mitochondrial homeostasis during reperfusion.
SN  - 2001-1326
ER  -