Endoplasmic reticulum-mitochondrial calcium transport contributes to soft extracellular matrix-triggered mitochondrial dynamics and mitophagy in breast carcinoma cells

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 trans-port by increasing endoplasmic reticulum (ER) calcium release and mitochondrial (MITO) calcium up -take. ER-MITO calcium transport promoted the recruitment of dynamin-related protein 1 (Drp1) to mito-chondria and phosphorylation at the serine 616 site, which induced mitochondrial fragmentation and Parkin/PINK1-mediated mitophagy. Furthermore, in vivo experiments demonstrated that soft ECM en-hanced 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 con-clusion, we revealed a new mechanism whereby ER-MITO calcium transport regulated mitochondrial dy-namics 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 mi-tochondrial fission and mitophagy by ER-MITO calcium transport. Furthermore, mitophagy partly attenu-ated 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 dynam-ics, providing valuable insights into ECM stiffness as a target for anti-tumor approaches, which could be beneficial for both biomechanics research and clinical applications. (c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

This study revealed a new mechanism by which ER-MITO calcium transport regulates mitochondrial dynamics and mitophagy through Drp1 translocation in response to soft substrates. Soft ECM increased calcium levels in tumor tissue and impaired mitochondrial dynamics. Inhibition of Drp1 activity enhanced soft ECM-induced tumor necrosis. These findings provide valuable insights into ECM stiffness as a potential target for antitumor therapy.