Mitophagy inhibitor liensinine suppresses doxorubicin-induced cardiotoxicity through inhibition of Drp1-mediated maladaptive mitochondrial fission

Xinyue Liang, Shuyi Wang, Lifeng Wang, Asli F. Ceylan, Jun Ren, Yingmei Zhang
Pharmacological Research2020
Doxorubicin (DOX) is one of the most effective antineoplastic drugs. However, its clinical application has been greatly limited due to the development of cardiotoxicity with DOX utilization. A number of theories have been postulated for DOX-induced cardiotoxicity with a pivotal contribution from unchecked (excess) mitophagy and mitochondrial fission. Liensinine (LIEN), a newly identified mitophagy inhibitor, strengthens the antineoplastic efficacy of DOX although its action on hearts remains elusive. This study was designed to examine the effect of LIEN on DOX-induced cardiotoxicity and the underlying mechanisms involved with a focus on mitochondrial dynamics. Our data revealed that LIEN alleviated DOX-induced cardiac dysfunction and apoptosis through in- hibition of dynamin-related protein 1 (Drp1)-mediated excess (unchecked) mitochondrial fission. LIEN treat- ment decreased Drp1 phosphorylation at Ser616 site, inhibited mitochondrial fragmentation, mitophagy (as- sessed by TOM20 and TIM23), oxidative stress, cytochrome C leakage, cardiomyocyte apoptosis, as well as improved mitochondrial function and cardiomyocyte contractile function in DOX-induced cardiac injury. In DOX-challenged neonatal mouse ventricular myocytes (NMVMs), LIEN-suppressed Drp1 phosphorylation, mi- tochondrial fragmentation, and apoptosis were blunted by Rab7 overexpression, the effect of which was reversed by the ERK inhibitor U0126. Moreover, activation of ERK or Drp1 abolished the protective effects of LIEN on cardiomyocyte mechanical anomalies. These data shed some lights towards understanding the role of LIEN as a new protective agent against DOX-associated cardiotoxicity without compromising its anti-tumor effects. 1.
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