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

Abstract

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 Drosophila melanogaster to identify genetic changes that confer resistance to cisplatin-induced neuronal damage but not in the rapidly dividing cells of the ovary. The Drosophila strain attP40, used as a genetic background for the creation of RNAi lines, is resistant to cisplatin damage compared with the similar attP2 background strain. attP40 flies have reduced mRNA expression of ND-13A, a component of the mitochondria electron transport chain complex I. Reduction of ND-13A 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 attP40 flies function similarly to control attP2 mitochondria under normal conditions. Mitochondria are damaged by cisplatin, leading to reduced activity, but attP40 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-1a, 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.

The effect ofDrosophila attP40background on the glomerular organization of Or47b olfactory receptor neurons

“…2022). In addition, this study also reported defects in muscle nuclei spacing in larval stages in the attP40 homozygous background, which phenocopies Msp300 mutants ( van der G raaf et al . 2022).…”

“…Thus, use of full animal mutants or MARCM based clonal mutant analysis should be coupled with RNAi-based phenotypic analyses. Though the underlying genetic reasons remain elusive, studies demonstrated that the attP40 landing site on chromosome II affects the expression of multiple genes (GROEN et al 2022; VAN DER GRAAF et al 2022). Additional omics-based experiments in the future will be needed to determine all the genetic lesions in the attP40 strain that underly many phenotypic defects observed in this background.…”

“…2022). These results suggest that attP40 docking site and attP40 -based transgenes are insertional mutations of Msp300 gene ( van der G raaf et al . 2022).…”

“…Indeed, recent studies have raised issues related to landing site-associated effects. For example, van der Graaf et al showed flies bearing two copies of attP40 -derived insertions also show decreased Msp300 transcript levels ( van der G raaf et al . 2022).…”

Roles for Mitochondrial Complex I Subunits in Regulating Synaptic Transmission and Growth

“…Additionally, we used UAS-RNAi lines as a screening tool. A recent study demonstrated that RNAi lines with an attP40 insertion site may have a reduction in adjacent ND-13A expression, and ND-13A encodes an MCI accessory subunit ( Groen et al, 2022 ). For our work, this could mean that any attP40 lines are sensitized to MCI impairment and potentially lower neurotransmission.…”