Abstract：
Doxorubicin (Dox), an anthracycline antibiotic, is an anticancer drug that inhibits DNA replication and cellular metabolic processes in cancer cells with high proliferative potential. However, Dox causes severe side effects, including myocardial damage and heart failure, but the molecular mechanism underlying Dox-induced myocardial injury remains uncertain. In the present study, we evaluated the effects of Dox on the mitochondrial quality control system and regulation of mitochondrial respiration and autophagy in an in vitro rat myoblast H9c2 cell culture model using western blotting, immunohistochemistry, the Seahorse XF24 system, and flow cytometry. Our results showed that Dox did not impair the initiation of autophagic flux or the functions of lysosomes; however, Dox affected the mitochondrial quality control system, leading to a fission-dominant morphology and impaired regulation of mitochondrial respiration, thereby increasing oxidative stress and inhibited progression of autophagy, particularly the fusion of autophagosomes with lysosomes. This inhibition caused a significant decrease in the formation of autolysosomes and was responsible for the accumulation of dysfunctional mitochondria and subsequent increase in oxidative stress, eventually leading to increased myocardial cell death.
摘要：
阿霉素（Dox），蒽环类抗生素,是一种抑制癌细胞DNA复制和细胞代谢过程的抗癌药物，具有很高的增殖潜力。然而,Dox会导致严重的副作用，包括心肌损伤和心力衰竭,但Dox诱导心肌损伤的分子机制仍不确定。在本研究中,我们使用westernblotting评估了Dox对体外大鼠成肌细胞H9c2细胞培养模型中线粒体质量控制系统以及线粒体呼吸和自噬调节的影响，免疫组织化学，海马XF24系统,和流式细胞术。我们的结果表明，Dox不会损害自噬通量的启动或溶酶体的功能；然而，Dox影响了线粒体质量控制系统，导致裂变主导形态和线粒体呼吸调节受损，从而增加氧化应激并抑制自噬的进展，特别是自噬体与溶酶体的融合。这种抑制作用导致自溶酶体形成的显着减少，并导致功能失调的线粒体积累和随后的氧化应激增加。最终导致心肌细胞死亡增加。
