Tumor susceptibility gene 101 ameliorates endotoxin-induced cardiac dysfunction by enhancing Parkin-mediated mitophagy.

Abstract

Cardiac mitochondrial damage and subsequent inflammation are hallmarks of endotoxin-induced myocardial depression. Activation of the Parkin/PTEN-induced kinase 1 (PINK1) pathway has been shown to promote autophagy of damaged mitochondria (mitophagy) and to protect from endotoxin-induced cardiac dysfunction. Tumor susceptibility gene 101 (TSG101) is a key member of the endosomal recycling complexes required for transport, which may affect autophagic flux. In this study, we investigated whether TSG101 regulates mitophagy and influences the outcomes of endotoxin-induced myocardial dysfunction. TSG101 transgenic and knockdown mice underwent endotoxin/lipopolysaccharide treatment (10 μg/g) and were assessed for survival, cardiac function, systemic/local inflammation, and activity of mitophagy mediators in the heart. Upon endotoxin challenge and compared with WT mice, TSG101 transgenic mice exhibited increased survival, preserved cardiac contractile function, reduced inflammation, and enhanced mitophagy activation in the heart. By contrast, TSG101 knockdown mice displayed opposite phenotypes during endotoxemia. Mechanistically, both coimmunoprecipitation assays and coimmunofluorescence staining revealed that TSG101 directly binds to Parkin in the cytosol of myocytes and facilitates translocation of Parkin from the cytosol to the mitochondria. Our results indicate that TSG101 elevation could protect against endotoxin-triggered myocardial injury by promoting Parkin-induced mitophagy.

• Authors: Kobina Essandoh, Xiaohong Wang, Wei Huang, Shan Deng, George Gardner, Xingjiang Mu, Yutian Li, Evangelia G Kranias, Yigang Wang, Guo-Chang Fan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 48 Pg. 18057-18068 (11 29 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 31619520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Essandoh et al.

Chemical References

• DNA-Binding Proteins
• Endosomal Sorting Complexes Required for Transport
• Lipopolysaccharides
• Transcription Factors
• Tsg101 protein
• Ubiquitin-Protein Ligases
• parkin protein
• Protein Kinases
• PTEN-induced putative kinase

Topics

• Animals
• DNA-Binding Proteins (genetics, metabolism)
• Endosomal Sorting Complexes Required for Transport (genetics, metabolism)
• Heart Diseases (chemically induced, genetics, metabolism, pathology)
• Lipopolysaccharides (toxicity)
• Male
• Mice
• Mice, Knockout
• Mitochondria, Heart (genetics, metabolism, pathology)
• Mitophagy (drug effects, genetics)
• Myocardial Contraction (drug effects, genetics)
• Protein Kinases (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)