Mitophagy and Ubiquitination Coordinate Context‐Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion

ABSTRACT Metastatic invasiveness emerges from coordinated intrinsic programs and microenvironmental cues that converge on mitochondrial quality control (MQC). Here, we use “context” to denote stage‐ and site‐aware constellations of tumor‐intrinsic states (e.g., mtROS tone, mtDNA integrity, epigenetic wiring, cellular stiffness, oncogenic mutations) and extrinsic landscapes (oxygen–nutrient availability, ECM mechanics, stromal/inflammatory signals). These axes jointly shape mitochondrial adaptation by tuning bioenergetics, redox balance, metabolic plasticity, fission–fusion dynamics, mechanosensitive hubs, and Ca 2 + homeostasis. As pressures intensify, mitochondrial vulnerabilities—such as mtDNA compromise and mtUPR activation—signal the engagement of mitophagy to preserve organelle fitness under stress. Through these coupled changes in mitochondrial performance and stress responses, context governs EMT/MET plasticity and transitions across migratory, invasive, and proliferative states. Mechanistically, ubiquitin conjugation, via E3 ligases and deubiquitinases, serves as an integrating conduit that links mitochondrial remodeling and mitophagy to cytoskeletal reprogramming and invasive behavior. This ubiquitin–mitochondria interface therefore represents a coherent therapeutic entry point; translational strategies including PROTAC‐enabled targeting and selective E3/DUB or mitophagy‐pathway modulators may rebalance pathological ubiquitin signaling, restore mitochondrial homeostasis, and constrain tumor dissemination.