异常的线粒体裂变/融合动力学通常与包括癌症在内的病理学相关。我们发现裂变蛋白 Drp1 (DNM1L) 的选择性剪接变体导致肿瘤细胞中线粒体裂变/融合调节的复杂性。相对于其他转录本，缺乏外显子 16 的 Drp1 选择性剪接变体的高肿瘤表达与卵巢癌患者的不良预后相关。缺乏外显子 16 会导致 Drp1 定位于微管，并减少与线粒体裂变位点的关联，最终导致线粒体网络融合、呼吸作用增强、代谢变化以及体外和体内促肿瘤表型增强。这些效应被设计用于特异性靶向缺乏外显子 16 的内源表达转录物的 siRNA 所抑制。此外，缺乏外显子 16 会消除线粒体对促凋亡刺激的裂变，并导致对化疗药物的敏感性降低。这些数据强调了 Drp1 选择性剪接的病理生理学重要性，强调了改变肿瘤细胞中 Drp1 剪接变体相对表达的不同功能和后果，并强烈建议在未来以 Drp1 为重点的研究中考虑选择性剪接。© 2024。作者（ s）。

Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.© 2024. The Author(s).