The Disrupted Mitochondrial Quality Control Network: A Unifying Mechanism and Therapeutic Target for Chemotherapy-Induced Multi-Organ Toxicity

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.