Mitochondrial Dynamics and Bioenergetic Reprogramming: Drivers of Cancer Therapy Resistance.
Mitochondria, often referred to as the powerhouses of the cell, play a pivotal role in maintaining cellular homeostasis through the regulation of energy production, redox balance, and apoptosis. Recent evidence highlights the significance of mitochondrial dynamics, fusion, fission, biogenesis, and mitophagy, enabling cells to adapt to changing physiological and environmental conditions. Dysregulation of these dynamic processes alters mitochondrial function, promoting metabolic reprogramming, evasion of apoptosis, and resistance to chemotherapy. Specifically, enhanced mitochondrial fission is often linked to increased metabolic flexibility and resistance to cell death, while aberrant fusion supports mitochondrial quality control under cellular stress. Additionally, tumour cells also exhibit bioenergetic flexibility, dynamically switching between OXPHOS and glycolysis to meet energy demands and overcome therapeutic stress. This metabolic change influences ROS levels, directly affecting the efficacy of anticancer agents in cancer cells. Such adaptations are now recognised as hallmarks of drug-resistant cancers. This review explores the mechanistic interplay between mitochondrial dynamics and cancer bioenergetics, emphasising how these processes contribute to drug resistance. We also focus on emerging therapeutic strategies, particularly smallmolecule inhibitors targeting mitochondrial fusion and fission that offer promising potential to restore chemosensitivity and disrupt cancer cell survival. A deeper understanding of mitochondrial behaviour in cancer may reveal novel therapeutic targets for the development of more effective and durable cancer treatments.