MST1 mediates doxorubicin-induced cardiomyopathy by SIRT3 downregulation

• DOI: 10.1007/s00018-023-04877-7
• Publication Date: 2023-08-11T08:02:41Z
• Authors: Leonardo Schirone; Daniele Vecchio; Valentina Valenti; Maurizio Forte; Michela Relucenti; Annalisa Angelini; Tania Zaglia; Sonia Schiavon; Luca D’Ambrosio; Gianmarco Sarto; Rosita Stanzione; Elisa Mangione; Selenia Miglietta; Anna Di Bona; Marny Fedrigo; Alessandra Ghigo; Francesco Versaci; Vincenzo Petrozza; Simona Marchitti; Speranza Rubattu; Massimo Volpe; Junichi Sadoshima; Luigi Frati; Giacomo Frati; Sebastiano Sciarr...
• Keywords: SIRT3

Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying development DOX-induced heart need to be addressed. This study aims test whether serine/threonine kinase MST1, Hippo pathway component, contributes myocardial injury. C57BL/6J WT mice and cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections DOX, reaching final cumulative dose 18 mg/kg. Echocardiographic, histological biochemical analyses were performed six weeks after first DOX administration. The effects inhibition on cardiomyocyte injury also tested vitro. signaling was significantly activated cardiomyocytes response vitro vivo. Wild-type (WT) treated developed cardiac dysfunction mitochondrial abnormalities. these detrimental abolished (DN-MST1) or XMU-MP-1, specific inhibitor, indicating that attenuates dysfunction. led significant downregulation levels SIRT3, deacetylase involved protection, mice, which rescued by inhibition. Pharmacological SIRT3 blunted protective inhibition, mediates cytotoxic activation treatment. Finally, we found upregulation human tissue cancer DOX. In summary, cardiomyopathy through downregulation.