title: Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy.
abstract: Sensory neuropathy is a relevant side effect of the antineoplastic agent cisplatin. Mitochondrial damage is assumed to play a critical role in cisplatin-induced peripheral neuropathy, but the pathomechanisms underlying cisplatin-induced mitotoxicity and neurodegeneration are incompletely understood. In an animal model of cisplatin-induced neuropathy, we determined in detail the extent and spatial distribution of mitochondrial damage during cisplatin treatment. Changes in the total number of axonal mitochondria during cisplatin treatment were assessed in intercostal nerves from transgenic mice that express cyan fluorescent protein. Further, we explored the impact of cisplatin on the expression of nuclear encoded molecules of mitochondrial fusion and fission, including mitofusin-2 (MFN2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (DRP1). Cisplatin treatment resulted in a loss of total mitochondrial mass in axons and in an abnormal mitochondrial morphology including atypical enlargement, increased vacuolization, and loss of cristae. These changes were observed in distal and proximal nerve segments and were more prominent in axons than in Schwann cells. Transcripts of fusion and fission proteins were reduced in distal nerve segments. Significant reduced expression levels of the fusion protein MFN2 was detected in nerves of cisplatin-exposed animals. In summary, we provide for the first time an evidence that cisplatin alters mitochondrial dynamics in peripheral nerves. Loss of MFN2, previously implicated in the pathogenesis of other neurodegenerative diseases, also contributes to the pathogenesis in cisplatin-induced neuropathy.
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Ilja
authors.initials: I
authors.lastname: Bobylev
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Abhijeet R
authors.initials: AR
authors.lastname: Joshi
authors.affiliation: Department of Anatomy I, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Barham
authors.affiliation: Department of Anatomy I, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Wolfram F
authors.initials: WF
authors.lastname: Neiss
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany. helmar.lehmann@uk-koeln.de.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. helmar.lehmann@uk-koeln.de.
authors.forename: Helmar C
authors.initials: HC
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D004195:Disease Models, Animal; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; C498809:Opa1 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins; D002945:Cisplatin
keywords: CIPN; Cisplatin neurotoxicity; DRG; Fusion and fission; Mitochondria