阿霉素 (DOX) 引起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 DOX 破坏线粒体裂变和融合之间平衡的机制仍存在争议。在本研究中，我们观察到 DOX 诱导多种心血管细胞系线粒体伸长。从机械角度来看，DOX不仅下调线粒体融合蛋白，包括线粒体融合蛋白1/2（MFN1/2）和视神经萎缩1（OPA1），而且还诱导动力相关蛋白1（Drp1）的运动性降低及其637丝氨酸的磷酸化，这使得可以抑制线粒体分裂。有趣的是，DOX 未能诱导与蛋白激酶 A (PKA) 抑制剂 H89 共同处理或表达磷酸缺陷 Drp1-S637A 变体的心肌细胞中的线粒体伸长。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，这可以通过敲除OPA1来进行表型复制。因此，我们推测DOX同时抑制线粒体裂变和融合，但使线粒体融合主导线粒体动力学，导致线粒体伸长为主要表现。值得注意的是，通过抑制 Drp1-S637 磷酸化或敲低 OPA1 来阻断线粒体伸长会加剧 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的平衡紊乱，作为一种适应性反应并提供针对 DIC 的保护。版权所有 © 2024。由 Elsevier Inc. 出版。

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 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 both 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.Copyright © 2024. Published by Elsevier Inc.