Neuraminidase1 Inhibitor Protects Against Doxorubicin-Induced Cardiotoxicity via Suppressing Drp1-Dependent Mitophagy

Yating Qin,Chao Lv,Li Lu,Chen Chen,Xinxin Zhang,Xinyun Ji,Weibin Ruan,Xiaomei Guo,Xiangyu Xu

doi:10.3389/fcell.2021.802502

Abstract

Anthracyclines, such as doxorubicin (DOX), are among the effective chemotherapeutic drugs for various malignancies. However, their clinical use is limited by irreversible cardiotoxicity. This study sought to determine the role of neuraminidase 1 (NEU1) in DOX-induced cardiomyopathy and the potential cardio-protective effects of NEU1 inhibitor oseltamivir (OSE). Male Sprague–Dawley (SD) rats were randomized into three groups: control, DOX, and DOX + OSE. NEU1 was highly expressed in DOX-treated rat heart tissues compared with the control group, which was suppressed by OSE administration. Rats in the DOX + OSE group showed preserved cardiac function and were protected from DOX-induced cardiomyopathy. The beneficial effects of OSE were associated with the suppression of dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and mitophagy. In detail, the elevated NEU1 in cardiomyocytes triggered by DOX increased the expression of Drp1, which subsequently enhanced mitochondrial fission and PINK1/Parkin pathway-mediated mitophagy, leading to a maladaptive feedback circle towards myocardial apoptosis and cell death. OSE administration selectively inhibited the increased NEU1 in myocardial cells insulted by DOX, followed by reduction of Drp1 expression, inhibition of PINK1 stabilization on mitochondria, and Parkin translocation to mitochondria, thus alleviating excessive mitochondrial fission and mitophagy, alleviating subsequent development of cellular apoptotic process. This work identified NEU1 as a crucial inducer of DOX-induced cardiomyopathy by promoting Drp1-dependent mitochondrial fission and mitophagy, and NEU1 inhibitor showed new indications of cardio-protection against DOX cardiotoxicity.

Highlights

Doxorubicin (DOX), an extensively prescribed and the most potent chemotherapeutic agent for various malignancies, still remains footstones in oncotherapy combined with emerging targeted drugs
DOX exposure resulted in an elevated level of Neu5AC, a kind of metabolite whose generation was predominantly regulated by neuraminidase 1 (NEU1), in both blood serum and myocardial tissue compared with the control group, and the elevated level of Neu5AC was significantly attenuated post-OSE treatment (Figure 1D, E)
By immunohistochemical staining, it was revealed that NEU1 expression was dramatically increased in myocardial tissues of DOX-treated rats in comparison with the control group, which was significantly attenuated by OSE co-treatment (Figure 1F)

Summary

Introduction

Doxorubicin (DOX), an extensively prescribed and the most potent chemotherapeutic agent for various malignancies, still remains footstones in oncotherapy combined with emerging targeted drugs. Mitochondrial fission occurs in coordination with mitophagy (Morales et al, 2020), which is a selective form of autophagy that targets elimination of damaged or unfunctional mitochondria. When excessive mitochondrial fission occurs, the number of functional mitochondria is extensively reduced along with an accumulation of mitochondrial fragmentations. Upon prolonged stress, mitophagy can be detrimental to the heart by aggravating mitochondrial damage and accelerating cellular death via excessive self-consumption, resulting in cardiac dysfunction (Morales et al, 2020). A recently published study (Catanzaro et al, 2019) identified that Drp knockdown could attenuate DOX-induced accelerated mitophagy flux, and Drp1deficient mice were protected from DOX-induced cardiac damage, strongly confirming the role of Drp1-dependent mitophagy in DOX cardiotoxicity

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Results

Conclusion