Mitochondria-associated programmed cell death in colorectal cancer: molecular mechanisms, metabolic plasticity, and therapeutic opportunities.

Mitochondria integrate bioenergetics, redox homeostasis, calcium signaling, metabolite synthesis, organelle quality control, innate immune sensing, and regulated cell death. In colorectal cancer (CRC), mitochondrial function is not simply suppressed by aerobic glycolysis; rather, tumor cells dynamically redistribute flux between glycolysis, oxidative phosphorylation, glutaminolysis, fatty-acid metabolism, and the mevalonate pathway to meet stage- and treatment-specific demands. This metabolic plasticity determines whether mitochondrial stress is buffered or converted into a lethal signal. Here, we critically synthesize recent evidence linking mitochondrial bioenergetics, reactive oxygen species (ROS), mitophagy, fusion-fission dynamics, mitochondrial DNA (mtDNA) damage and release, mitochondrial biogenesis, and oncogenic signaling to apoptosis and non-apoptotic forms of programmed cell death, including ferroptosis, pyroptosis, necroptosis, PANoptosis, and cuproptosis. We further discuss mtDNA sensors-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), Toll-like receptor 9 (TLR9), NOD-like receptor family pyrin domain-containing 3 (NLRP3), and Z-DNA-binding protein 1 (ZBP1)-as links between mitochondrial injury, tumor-cell death, and antitumor immunity. Particular attention is given to B-cell lymphoma 2 (BCL-2) homology 3 (BH3) mimetics, metabolic inhibitors, patient-derived organoids (PDO), patient-derived organoid xenografts (PDOX), and immunocompetent models. Current evidence supports mitochondria as a therapeutically actionable network, but also reveals major context dependencies related to tumor genotype, cell state, treatment schedule, immune competence, and normal-tissue mitochondrial requirements. Biomarker-guided combinations and model systems that preserve patient heterogeneity will therefore be essential for clinical translation.