Mitochondrial metabolism in cancer stem cells (CSCs): molecular and diagnostic implications

Cancer stem cells (CSCs) are a self-renewing population often linked to tumor initiation, metastasis, relapse, and resistance to therapy. While bulk tumor cells are often dependent on glycolysis, CSCs demonstrate metabolic plasticity can switch between glycolysis and OXPHOS (oxidative phosphorylation) depending on context. Mitochondria buffer against stress and allow for a metabolic reprogramming towards apoptosis evasiveness, making mitochondrial function crucial to CSC survival. The acquisition of stem-like traits coincides with the rewiring of mitochondrial metabolism, as newly emerging CSCs intermittently upregulate respiration, ROS detoxification, and metabolic plasticity to satisfy cellular demands. Several regulators converge on this mitochondrial metabolism axis. For instance, the co-activator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and partner estrogen-related receptor α (ERRα) promote mitochondria biogenesis and OXPHOS while promoting tumor sphere formation and expression of stemness genes. Conversely, knockdown of PGC-1α reduces sphere formation and stemness. Similarly, a crucial process - mitophagy via AMP-activated protein kinase (AMPK) and related kinases regulate organelle turnover and quality control to promote CSC viability against stress. Mitochondrial dynamics (fission/fusion) also decides the fate of CSCs. The CSC metabolism is further influenced by the tumor microenvironment (TME). Hypoxia-inducible transcription factors, along with tumor stromal signals such as CAF-derived metabolites induce metabolic rewiring and strengthen antioxidant defenses in CSCs, thereby making it easier for CSCs to survive in unfavourable niches. The abundance of mitochondrial DNA and basal respiratory activity has been linked to CSC features such as increased ATP, stem cell markers and chemoresistance. Over the past few years, significant progress has been made in targeting mitochondrial metabolism of CSCs, yet is still a developing area with tremendous therapeutic scope. More research is required to identify mitochondrial vulnerabilities that are specific to therapy and then translate those findings into effective, precision-based cancer treatments. In this review, we try to provide a comprehensive overview of mitochondrial metabolism in regulating behaviour of CSCs, origin and characteristics of CSCs, the metabolic reprogramming for OXPHOS and glycolytic flexibility, molecular regulators of mitochondrial function, mitochondrial dynamics in stemness pathways and how the TME regulates these processes. We also review novel diagnostic techniques and therapies that target mitochondrial vulnerabilities to eliminate CSCs and provide better clinical outcomes.