Genetic Reduction of Mitochondria Complex I Subunits is Protective against Cisplatin-Induced Neurotoxicity in .

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent side effect of widely used platinum-based anticancer agents. There are few predictable risk factors with which to identify susceptible patients. Effective preventive measures or treatments are not available. Here, we have used a model of CIPN in to identify genetic changes that confer resistance to cisplatin-induced neuronal damage but not in the rapidly dividing cells of the ovary. The strain , used as a genetic background for the creation of RNAi lines, is resistant to cisplatin damage compared with the similar background strain. flies have reduced mRNA expression of , a component of the mitochondria electron transport chain complex I. Reduction of via neuron-specific RNAi leads to resistance to the dose-dependent climbing deficiencies and neuronal apoptosis observed in control flies. These flies are also resistant to acute oxidative stress, suggesting a mechanism for resistance to cisplatin. The mitochondria of flies function similarly to control mitochondria under normal conditions. Mitochondria are damaged by cisplatin, leading to reduced activity, but mitochondria are able to retain function and even increase basal respiration rates in response to this stress. This retained mitochondrial activity is likely mediated by Sirt1 and peroxisome proliferator-activated receptor gamma coactivator-1α, and is key to cisplatin resistance. Our findings represent the potential for both identification of susceptible patients and prevention of CIPN through the targeting of mitochondria. Chemotherapy-induced peripheral neuropathy is a major, debilitating side effect of many platinum-based cancer drugs. There are few available screening tools to identify patients at risk, and there are no effective treatments. Here, we report a novel genetic change that confers resistance to cisplatin-induced neurotoxicity in a model while preserving the toxic effect in rapidly dividing cells. This work has the potential to influence patient susceptibility testing and development of novel CIPN preventive treatments.