Targeting Mitochondrial Vulnerabilities in Chronic Myeloid Leukemia: From Pathobiology to Novel Therapeutic Opportunities

Background: Mitochondria are multifunctional organelles that play a central role in maintaining cellular homeostasis by regulating energy metabolism, reactive oxygen species (ROS) generation, ion homeostasis, and apoptotic signaling. Dynamic processes such as mitochondrial fission, fusion, and intracellular trafficking enable cells to adapt to metabolic and environmental stress. Growing evidence indicates that dysregulation of these processes is a hallmark of cancer, contributing to metabolic reprogramming, redox imbalance, evasion of apoptosis, and disease progression. This narrative review aims to discuss the role of mitochondrial alterations in the pathophysiology of chronic myeloid leukemia (CML) and their potential therapeutic implications. Methods: Original research articles published between 2010 and 2025 were considered in this narrative review. The selected studies were critically discussed and categorized into three principal thematic domains: mitochondrial regulation of redox homeostasis, metabolic rewiring, and control of cell death pathways. Evidence was synthesized to elucidate the contribution of mitochondrial dysfunction to CML initiation, progression, and therapeutic resistance. Results: The reviewed studies highlight how mitochondrial abnormalities play a pivotal role in BCR-ABL1-driven leukemogenesis. Alterations in mitochondrial metabolism and ROS signaling support sustained proliferative signaling, promote genomic instability, and facilitate resistance to apoptosis. In addition, mitochondrial adaptations contribute to resistance to tyrosine kinase inhibitors (TKIs) and are essential for the persistence and survival of leukemic stem cells. Conclusions: Mitochondria emerge as central regulators of CML pathobiology. Therapeutic strategies targeting mitochondrial metabolism, redox homeostasis, and apoptotic signaling pathways represent promising approaches to overcoming TKI resistance and may improve clinical outcomes for patients with CML.