Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510000 Guangzhou, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Cardiovascular Institute, 510000 Guangzhou, China.
Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510000 Guangzhou, China.
Biochem Pharmacol. 2024 Nov;229:116495. doi: 10.1016/j.bcp.2024.116495. Epub 2024 Aug 17.
Doxorubicin (DOX)-induced cardiac damage remains a leading cause of death amongst cancer survivors. DOX-induced cardiotoxicity (DIC) is mediated by disturbed mitochondrial dynamics, but it remains debated that the mechanisms by which DOX disrupted equilibrium between mitochondrial fission and fusion. In the present study, we observed that DOX induced mitochondrial elongation in multiple cardiovascular cell lines. Mechanically, DOX not only downregulated the mitochondrial fusion proteins including Mitofusin 1/2 (MFN1/2) and Optic atrophy 1 (OPA1), but also induced lower motility of dynamin-related protein 1(Drp1) and its phosphorylation on 637 serine, which could inhibit mitochondrial fission. Interestingly, DOX failed to induce mitochondrial elongation in cardiomyocytes co-treated with protein kinase A (PKA) inhibitor H89 or expressing phosphodeficient Drp1-S637A variants. Besides, carbonyl cyanide 3-chlorophenylhydrazone (CCCP) was able to blocked the mitochondrial elongation induced by DOX treatment, which could be phenocopied by OPA1 knockdown. Therefore, we speculated that DOX inhibited mitochondrial fission and fusion simultaneously, yet enabled mitochondrial fusion dominate the mitochondrial dynamics, resulting in mitochondrial elongation as the main manifestation. Notably, blocking mitochondrial elongation by inhibiting Drp1-S637 phosphorylation or OPA1 knockdown aggravated DOX-induced cardiomyocytes death. Based on these results, we propose a novel mechanistic model that DOX-induced mitochondrial elongation is attributed to the equilibrium disturbance of mitochondrial dynamics, which serves as an adaptive response and confers protection against DIC.
多柔比星（DOX）诱导的心脏损伤仍然是癌症幸存者死亡的主要原因。DOX 诱导的心脏毒性（DIC）是由线粒体动力学紊乱介导的，但仍有争议的是，DOX 破坏线粒体分裂和融合之间平衡的机制。在本研究中，我们观察到 DOX 在多种心血管细胞系中诱导线粒体伸长。从机制上讲，DOX 不仅下调了线粒体融合蛋白，包括线粒体融合蛋白 1/2（MFN1/2）和视神经萎缩 1（OPA1），还诱导了动力相关蛋白 1（Drp1）及其 637 丝氨酸磷酸化的运动性降低，这可以抑制线粒体分裂。有趣的是，在与蛋白激酶 A（PKA）抑制剂 H89 共处理或表达磷酸缺陷 Drp1-S637A 变体的心肌细胞中，DOX 未能诱导线粒体伸长。此外，羰基氰化物 3-氯苯腙（CCCP）能够阻断 DOX 处理诱导的线粒体伸长，OPA1 敲低可模拟这种现象。因此，我们推测 DOX 同时抑制线粒体分裂和融合，但使线粒体融合主导线粒体动力学，导致线粒体伸长成为主要表现。值得注意的是，通过抑制 Drp1-S637 磷酸化或 OPA1 敲低阻断线粒体伸长会加重 DOX 诱导的心肌细胞死亡。基于这些结果，我们提出了一种新的机制模型，即 DOX 诱导的线粒体伸长归因于线粒体动力学平衡的干扰，这是一种适应性反应，可对抗 DIC。
