Drp1 剪接变体调控卵巢癌线粒体动力学和肿瘤进展。

IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-10-01 Epub Date: 2024-08-27 DOI:10.1038/s44319-024-00232-4
Zaineb Javed, Dong Hui Shin, Weihua Pan, Sierra R White, Amal Taher Elhaw, Yeon Soo Kim, Shriya Kamlapurkar, Ya-Yun Cheng, J Cory Benson, Ahmed Emam Abdelnaby, Rébécca Phaëton, Hong-Gang Wang, Shengyu Yang, Mara L G Sullivan, Claudette M St Croix, Simon C Watkins, Steven J Mullett, Stacy L Gelhaus, Nam Lee, Lan G Coffman, Katherine M Aird, Mohamed Trebak, Karthikeyan Mythreye, Vonn Walter, Nadine Hempel
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引用次数: 0

摘要

线粒体裂变/融合动力学异常经常与包括癌症在内的各种病症有关。我们的研究表明,裂变蛋白 Drp1(DNM1L)的替代剪接变体增加了肿瘤细胞线粒体裂变/融合调控的复杂性。与其他转录本相比,缺乏第 16 号外显子的 Drp1 替代剪接变体的肿瘤高表达与卵巢癌患者的不良预后有关。缺乏第 16 号外显子会导致 Drp1 定位于微管,减少与线粒体裂变位点的结合,最终导致线粒体网络融合、呼吸增强、新陈代谢改变以及体外和体内促肿瘤表型增强。这些效应会被设计为特异性靶向缺乏第 16 号外显子的内源性表达转录本的 siRNA 所抑制。此外,缺乏第 16 号外显子会抑制线粒体在促凋亡刺激下的分裂,并导致对化疗药物的敏感性降低。这些数据强调了 Drp1 替代剪接在病理生理学上的重要性,突出了改变肿瘤细胞中 Drp1 剪接变体的相对表达所产生的不同功能和后果,并强烈建议在今后以 Drp1 为重点的研究中考虑替代剪接。
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Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.

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.

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来源期刊
EMBO Reports
EMBO Reports 生物-生化与分子生物学
CiteScore
11.20
自引率
1.30%
发文量
267
审稿时长
1 months
期刊介绍: EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry. 
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