Osteosarcoma stem cells resist chemotherapy by maintaining mitochondrial dynamic stability via DRP1

Tian,Boren; Wu,Yaxuan; Du,Xiaoyun; Zhang,Yan

doi:10.3892/ijmm.2024.5451

Osteosarcoma stem cells resist chemotherapy by maintaining mitochondrial dynamic stability via DRP1

Authors:
- Boren Tian
- Yaxuan Wu
- Xiaoyun Du
- Yan Zhang
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Affiliations: MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat‑sen University, Guangzhou, Guangdong 510275, P.R. China, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat‑sen University, Guangzhou, Guangdong 510275, P.R. China
Published online on: October 29, 2024 https://doi.org/10.3892/ijmm.2024.5451
Article Number: 10
Copyright: © Tian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteosarcoma malignancy exhibits significant heterogeneity, comprising both osteosarcoma stem cells (OSCs) and non‑OSCs. OSCs demonstrate increased resistance to chemotherapy due to their distinctive cellular and molecular characteristics. Alterations in mitochondrial morphology and homeostasis may enhance chemoresistance by modulating metabolic and regulatory processes. However, the relationship between mitochondrial homeostasis and chemoresistance in OSCs remains to be elucidated. The present study employed high‑resolution microscopy to perform multi‑layered image reconstructions for a quantitative analysis of mitochondrial morphology. The results indicated that OSCs exhibited larger mitochondria in comparison with non‑OSCs. Furthermore, treatment of OSCs with cisplatin (CIS) or doxorubicin (DOX) resulted in preserved mitochondrial morphological stability, which was not observed in non‑OSCs. This finding suggested a potential association between mitochondrial homeostasis and chemoresistance. Further analysis indicated that dynamin‑related protein 1 (DRP1) might play a pivotal role in maintaining the stability of mitochondrial homeostasis in OSCs. Depletion of DRP1 resulted in the disruption of mitochondrial stability when OSCs were treated with CIS or DOX. Additionally, knocking out DRP1 in OSCs led to a reduction in chemoresistance. These findings unveil a novel mechanism underlying chemoresistance in osteosarcoma and suggest that targeting DRP1 could be a promising therapeutic strategy to overcome chemoresistance in OSCs. This provided valuable insights for enhancing treatment outcomes among patients with osteosarcoma.

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