Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, PR China.
TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China.
Acta Biomater. 2023 Oct 1;169:192-208. doi: 10.1016/j.actbio.2023.07.060. Epub 2023 Aug 2.
Although mitochondrial morphology and function are considered to be closely related to matrix stiffness-driven tumor progression, it remains poorly understood how extracellular matrix (ECM) stiffness affects mitochondrial dynamics and mitophagy. Here, we found that soft substrate triggered calcium transport by increasing endoplasmic reticulum (ER) calcium release and mitochondrial (MITO) calcium uptake. ER-MITO calcium transport promoted the recruitment of dynamin-related protein 1 (Drp1) to mitochondria and phosphorylation at the serine 616 site, which induced mitochondrial fragmentation and Parkin/PINK1-mediated mitophagy. Furthermore, in vivo experiments demonstrated that soft ECM enhanced calcium levels in tumor tissue, Drp1 activity was required for soft ECM-induced mitochondrial dynamics impairment, and inhibition of Drp1 activity enhanced soft ECM-induced tumor necrosis. In conclusion, we revealed a new mechanism whereby ER-MITO calcium transport regulated mitochondrial dynamics and mitophagy through Drp1 translocation in response to soft substrates. These findings provide valuable insights into ECM stiffness as a potential target for antitumor therapy. STATEMENT OF SIGNIFICANCE: Here, we examined the relationship between substrate stiffness and mitochondrial dynamics by using polyacrylamide (PAA) substrates to simulate the stages of breast cancer or BAPN to reduce tumor tissue stiffness. The results elucidated that soft substrate triggered the recruitment of DRP1 and subsequent mitochondrial fission and mitophagy by ER-MITO calcium transport. Furthermore, mitophagy partly attenuated soft ECM-mediated tumor tissue necrosis and contributed to tumor survival in vivo. Our discoveries revealed the molecular mechanisms by which mechanical stimulation regulates mitochondrial dynamics, providing valuable insights into ECM stiffness as a target for anti-tumor approaches, which could be beneficial for both biomechanics research and clinical applications.
尽管线粒体形态和功能被认为与基质硬度驱动的肿瘤进展密切相关，但细胞外基质（ECM）硬度如何影响线粒体动力学和线粒体自噬仍知之甚少。在这里，我们发现软基质通过增加内质网（ER）钙释放和线粒体（MITO）钙摄取来触发钙转运。ER-MITO 钙转运促进了与线粒体相关的动力相关蛋白 1（Drp1）的募集和丝氨酸 616 位点的磷酸化，从而诱导线粒体分裂和 Parkin/PINK1 介导的线粒体自噬。此外，体内实验表明，软 ECM 增强了肿瘤组织中的钙水平，Drp1 活性是软 ECM 诱导的线粒体动力学损伤所必需的，抑制 Drp1 活性增强了软 ECM 诱导的肿瘤坏死。总之，我们揭示了一种新的机制，即 ER-MITO 钙转运通过 Drp1 易位来调节线粒体动力学和线粒体自噬，以响应软基质。这些发现为 ECM 硬度作为抗肿瘤治疗的潜在靶点提供了有价值的见解。
