Clin Transl Med. 2026 Oct;16(10):e70876. doi: 10.1002/ctm2.70876.
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.
PMID:42908113 | DOI:10.1002/ctm2.70876