ArticleCell biology and toxicology2026
SPSB3-mediated K48- and K63- linked ubiquitination and degradation of TUFM promote apoptosis induced by myocardial ischemia/reperfusion injury.
Article in Cell biology and toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Hypoxia, caused by various factors, significantly threatens human health by damaging the heart and cardiomyocytes. Revascularization strategies can sometimes precipitate adverse clinical outcomes due to myocardial ischemia/reperfusion (I/R) injury. The primary objective of this investigation was to explore the mechanism underlying myocardial I/R injury to identify novel alleviating strategies. CRISPR/Cas9 technology was used for high-throughput screening of hypoxia/reoxygenation (H/R)-tolerant genes; afterward, the genes were intersected with differentially expressed genes in the GSE61592 dataset. Subsequent validation identified SPRY domain-containing SOCS box protein 3 (SPSB3) as a critical gene that confers resistance to H/R injury. Increased apoptosis and worse heart function were observed in mouse and cardiomyocyte models of myocardial I/R injury. These pathological alterations coincided with a marked elevation in SPSB3 expression. Furthermore, SPSB3 inhibition substantially attenuated the myocardial I/R injury-induced increase in cardiomyocyte apoptosis, decrease in cardiac function, and mitochondrial dysfunction. To identify SPSB3 substrates, we combined the results from mass spectrometry, ubiquitin-modified proteomics, and the MitoCarta3.0 database (cardiac mitochondrial proteins), yielding six candidate molecules. Co-immunoprecipitation and western blot analyses indicated that SPSB3 may bind to Tu translation elongation factor, mitochondrial (TUFM). In SPSB3-knockdown cardiomyocytes, additional TUFM knockdown partially reversed the protective effect of SPSB3 knockdown alone. Additionally, MG132 and Cycloheximide treatment effectively inhibited TUFM degradation. Further amino acid site mutagenesis and other analyses revealed that SPSB3 inhibition prevents K48- and K63-linked ubiquitination at the K259 residue of TUFM and TUFM degradation, providing a promising therapeutic avenue for mitigating myocardial I/R injury.
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