Mitochondrial Dynamics in Cancer Therapy Response: Context-Dependent Adaptation, Cell Death, and Therapeutic Opportunities
4 affiliations
- 1Department of Biochemistry, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
- 2Department of Urology B, Hue Central Hospital, Hue 49135, Vietnam
- 3Department of Internal Medicine, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
- 4Department of Gynecology and Obstetrics, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
Abstract
Mitochondrial plasticity has emerged as a central determinant of cancer therapy response, enabling tumor cells to adapt to diverse metabolic, environmental, and therapeutic stresses. Among its key features, mitochondrial dynamics contributes to the balance between mitochondrial stress burden and compensatory capacity that shapes cell fate. We propose an adaptive-lethal threshold as a context-dependent conceptual framework describing the transition from reversible mitochondrial dynamics and cellular adaptation to persistent mitochondrial dysfunction and irreversible cell death commitment. Rather than representing a fixed molecular cutoff, this boundary reflects a context-dependent transition in which overall mitochondrial stress can no longer be adequately compensated to maintain cellular homeostasis. Furthermore, how this threshold is defined and reprogrammed in therapy resistance remains unresolved. In this review, we synthesize current advances to propose a framework in which mitochondrial dynamics govern cell fate through threshold-dependent mechanisms. We highlight key pathways across multiple cancer types, including reactive oxygen species (ROS) signaling, mitophagy, metabolic reprogramming, retrograde signaling, evasion of cell death, and interactions with the tumor microenvironment. Importantly, we discuss how context-dependent alterations in these processes can shift the balance between cytoprotective adaptation and irreversible mitochondrial dysfunction, contributing to therapy resistance or cell death. We further highlight emerging therapeutic strategies targeting mitochondrial dynamics and consider how modulation of mitochondrial dynamics can alter mitochondrial stress responses and influence the adaptive-lethal threshold, leading to cell sensitivity. Finally, we discuss key limitations and future directions in defining the context-dependent determinants of the adaptive-lethal transition and their implications for mitochondria-targeted therapies in cancer treatment.
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BibTeX
@article{do2026mitochondrial,
title = {{Mitochondrial Dynamics in Cancer Therapy Response: Context-Dependent Adaptation, Cell Death, and Therapeutic Opportunities}},
author = {Yen Thi Do and Kha Cong Le Bui and Jin Young Kim and So-Jin Shin and Ji Hae Seo},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219538},
url = {https://www.mdpi.com/1422-0067/27/21/9538},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mitochondrial Dynamics in Cancer Therapy Response: Context-Dependent Adaptation, Cell Death, and Therapeutic Opportunities
AU - Yen Thi Do
AU - Kha Cong Le Bui
AU - Jin Young Kim
AU - So-Jin Shin
AU - Ji Hae Seo
PY - 2026
DA - 2026/10/25
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219538
UR - https://www.mdpi.com/1422-0067/27/21/9538
AB - Mitochondrial plasticity has emerged as a central determinant of cancer therapy response, enabling tumor cells to adapt to diverse metabolic, environmental, and therapeutic stresses. Among its key features, mitochondrial dynamics contributes to the balance between mitochondrial stress burden and compensatory capacity that shapes cell fate. We propose an adaptive-lethal threshold as a context-dependent conceptual framework describing the transition from reversible mitochondrial dynamics and cellular adaptation to persistent mitochondrial dysfunction and irreversible cell death commitment. Rather than representing a fixed molecular cutoff, this boundary reflects a context-dependent transition in which overall mitochondrial stress can no longer be adequately compensated to maintain cellular homeostasis. Furthermore, how this threshold is defined and reprogrammed in therapy resistance remains unresolved. In this review, we synthesize current advances to propose a framework in which mitochondrial dynamics govern cell fate through threshold-dependent mechanisms. We highlight key pathways across multiple cancer types, including reactive oxygen species (ROS) signaling, mitophagy, metabolic reprogramming, retrograde signaling, evasion of cell death, and interactions with the tumor microenvironment. Importantly, we discuss how context-dependent alterations in these processes can shift the balance between cytoprotective adaptation and irreversible mitochondrial dysfunction, contributing to therapy resistance or cell death. We further highlight emerging therapeutic strategies targeting mitochondrial dynamics and consider how modulation of mitochondrial dynamics can alter mitochondrial stress responses and influence the adaptive-lethal threshold, leading to cell sensitivity. Finally, we discuss key limitations and future directions in defining the context-dependent determinants of the adaptive-lethal transition and their implications for mitochondria-targeted therapies in cancer treatment.
SN - 1422-0067
ER -