The Disrupted Mitochondrial Quality Control Network: A Unifying Mechanism and Therapeutic Target for...

Chemotherapy remains a cornerstone of systemic cancer treatment, yet dose-limiting toxicities-cardiotoxicity, neurotoxicity, and nephrotoxicity-affect 40-80% of patients, interrupt 20-30% of treatment cycles, and double long-term mortality. We propose that these seemingly distinct organ toxicities converge on a single mechanism: selective disruption of the MQC network. MQC comprises five interdependent modules-biogenesis, dynamics, mitophagy, proteostasis, and the recently characterized migrasome-mediated mitocytosis-collectively maintaining ATP supply, redox balance, and Ca²⁺ homeostasis in high-demand tissues. Chemotherapeutics such as anthracyclines, platinum agents, and taxanes simultaneously repress PGC-1α-driven biogenesis, hyperactivate Drp1-mediated fission, impair autophagosome-lysosome fusion, and inhibit mitocytosis, triggering mitochondrial collapse, ROS overflow, and cell death. This first-in-field review delineates organ-specific MQC pathways and catalogs druggable interventions-including small molecules, natural products, and nano-delivery systems-that restore MQC checkpoints. We present an integrated "MQC disruption-multi-organ toxicity-targeted intervention" framework, identifying Drp1 hyperactivation, late-stage mitophagy arrest, and mitocytosis inhibition as core therapeutic nodes. Targeting these pathways offers a promising strategy to decouple anticancer efficacy from off-target toxicity, potentially enabling optimized dosing, reducing treatment discontinuation, and improving long-term prognosis. Most MQC-targeted agents, however, remain in preclinical or early-phase trials.