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

## TL;DR

This paper identifies mitochondrial quality control network disruption as a common cause of chemotherapy-induced organ damage and suggests ways to protect organs without reducing cancer treatment effectiveness.

## Contribution

The paper introduces the mitochondrial quality control (MQC) network as a unifying mechanism for chemotherapy-induced toxicity and proposes targeted interventions.

## Key findings

- Chemotherapy disrupts five core components of the mitochondrial quality control (MQC) network.
- Treatments like small molecules and nano-delivery systems can repair the MQC network and protect organs.
- Targeting MQC disruption could improve chemotherapy regimens and reduce side effects.

## Abstract

Chemotherapy is essential for treating cancer, but it often severely damages vital organs such as the heart, nerves, and kidneys, leading to treatment interruptions and reduced quality of life. This study aimed to identify a shared cause of these toxicities and potential protective strategies. We found that the common driver is damage to the mitochondrial quality control (MQC) network—a system that maintains the health of mitochondria, the cell’s energy powerhouses. Chemotherapy disrupts five core components of this network. We also identified treatments, including certain small molecules, natural products, and nano-delivery systems, that can repair the MQC network and protect organs without compromising chemotherapy’s anticancer efficacy. These findings could help refine chemotherapy regimens, reduce side effects, and improve long-term outcomes for cancer patients, offering meaningful progress in clinical care.

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.