title: Cisplatin induces mitochondrial deficits in Drosophila larval segmental nerve.
abstract: Cisplatin is an effective chemotherapy drug that induces peripheral neuropathy in cancer patients. In rodent dorsal root ganglion neurons, cisplatin binds nuclear and mitochondrial DNA (mtDNA) inducing DNA damage and apoptosis. Platinum-mtDNA adducts inhibit mtDNA replication and transcription leading to mitochondrial degradation. Cisplatin also induces climbing deficiencies associated with neuronal apoptosis in adult Drosophila melanogaster. Here we used Drosophila larvae that express green fluorescent protein in the mitochondria of motor neurons to observe the effects of cisplatin on mitochondrial dynamics and function. Larvae treated with 10μg/ml cisplatin had normal survival with deficiencies in righting and heat sensing behavior. Behavior was abrogated by, the pan caspase inhibitor, p35. However, active caspase 3 was not detected by immunostaining. There was a 27% decrease in mitochondrial membrane potential and a 42% increase in reactive oxygen species (ROS) in mitochondria along the axon. Examination of mitochondrial axonal trafficking showed no changes in velocity, flux or mitochondrial length. However, cisplatin treatment resulted in a greater number of stationary organelles caused by extended pausing during axonal motility. These results demonstrate that cisplatin induces behavior deficiencies in Drosophila larvae, decreased mitochondrial activity, increased ROS production and mitochondrial pausing without killing the larvae. Thus, we identified particular aspects of mitochondrial dynamics and function that are affected in cisplatin-induced peripheral neuropathy and may represent key therapeutic targets.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jewel L
authors.initials: JL
authors.lastname: Podratz
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Knorr
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Koehler
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Forsythe
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Lambrecht
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Suzette
authors.initials: S
authors.lastname: Arias
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kiley
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Steinhoff
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Georgiy
authors.initials: G
authors.lastname: Yudintsev
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA. Electronic address: windebank.anthony@mayo.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Windebank
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007814:Larva; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D057897:Reflex, Righting / Q000187:drug effects; D013697:Thermosensing / Q000187:drug effects
chemical_list: D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D049452:Green Fluorescent Proteins; D053148:Caspase 3; D002945:Cisplatin
keywords: Apoptosis; Axonal trafficking; Cisplatin; Drosophila; Membrane potential; Mitochondria; Motor neuron