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Review
. 2023 Aug 3:10:1241225.
doi: 10.3389/fmolb.2023.1241225. eCollection 2023.

Targeting mitochondrial dynamics proteins for the treatment of doxorubicin-induced cardiotoxicity

Rui Chen  1 , Mengwen Niu  2 , Xin Hu  1 , Yuquan He  1
Affiliations
Review

Targeting mitochondrial dynamics proteins for the treatment of doxorubicin-induced cardiotoxicity

Rui Chen et al. Front Mol Biosci. .

Abstract

Doxorubicin (DOX) is an extensively used chemotherapeutic agent that can cause severe and frequent cardiotoxicity, which limits its clinical application. Although there have been extensive researches on the cardiotoxicity caused by DOX, there is still a lack of effective treatment. It is necessary to understand the molecular mechanism of DOX-induced cardiotoxicity and search for new therapeutic targets which do not sacrifice their anticancer effects. Mitochondria are considered to be the main target of cardiotoxicity caused by DOX. The imbalance of mitochondrial dynamics characterized by increased mitochondrial fission and inhibited mitochondrial fusion is often reported in DOX-induced cardiotoxicity, which can result in excessive ROS production, energy metabolism disorders, cell apoptosis, and various other problems. Also, mitochondrial dynamics disorder is related to tumorigenesis. Surprisingly, recent studies show that targeting mitochondrial dynamics proteins such as DRP1 and MFN2 can not only defend against DOX-induced cardiotoxicity but also enhance or not impair the anticancer effect. Herein, we summarize mitochondrial dynamics disorder in DOX-induced cardiac injury. Furthermore, we provide an overview of current pharmacological and non-pharmacological interventions targeting proteins involved in mitochondrial dynamics to alleviate cardiac damage caused by DOX.

Keywords: anticancer effect; cardiotoxicity; doxorubicin (Dox); mitochondrial dynamics; pharmacological and non-pharmacological interventions.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The mechanics of mitochondrial fission and fusion. Schematic representation of mitochondrial fusion and fission machinery and related cell function. (A) Mitochondrial dynamics-associated key mediators including pro-fission proteins (DRP1, FIS1, MFF, MiD49, MiD51, and MTF18) and pro-fusion proteins (MFN1, MFN2, and OPA1). (B) Mitochondrial fission is mainly regulated by the key player DRP1, OMM receptors (MFF, MiD49, MiD51 and FIS1), which are responsible for the recruitment of DRP1 from the cytosol to mitochondria. And ER wraps mitochondria and identifies the fission site, where DRP1 oligomerizes and induces mem-brane constriction. (C) Mitochondrial fusion relies on MFN1 and MFN2 located on the OMM to tether the OMMs of mitochondria, and on OPA1 to mediate fusion of IMM. (D) Mitochondrial fate is regulated by fission and fusion to adapt mitochondrial morphology to different stresses. Fission constricts and severs one mitochondrion to daughter mitochondria for cell division or fragmented mitochondria for removal by mitophagy and renewal by fusion into an elongated organelle.
FIGURE 2
FIGURE 2
Mitochondrial Dynamics Disorders in doxorubicin (DOX)-induced Cardiac Injury. By controlling proteins involved in mitochondrial fission and fusion, DOX treatment tilts the mitochondrial dynamic balance toward fission, resulting in abnormal mitochondrial structure that ultimately causes oxidative stress, mitochondrial dysfunction, impaired auto/mitophagy, cardiomyocyte apoptosis and cardiac injury.
FIGURE 3
FIGURE 3
Schematic figure showing that promoting MFN2-mediated mitochondrial fusion induces a similar metabolic transition from glycolysis to OXPHOS in cardiomyocytes and tumor cells, alleviating DOX-induced cardiotoxicity while increasing tumor cell death.
FIGURE 4
FIGURE 4
The mechanism of pharmacological strategies and exercise targeting mitochondrial dynamics proteins for DOX-induced cardiotoxicity. Inhibiting mitochondrial fission by targeting mitochondrial fission protein DRP1 mainly or promoting mitochondrial fusion by targeting mitochondrial fusion proteins like MFN1/2 and Opa1 via pharmacological and non-pharmacological strategies exerts cardioprotection against DOX.
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Grants and funding

The research leading to these results has received funding from Department of Health of Jilin Province (2015Z012) and Jilin Provincial Department of Science and Technology (YDZJ202301ZYTS516). The financial support was received by YH.