Universität zu Köln

Bobylev, Ilja, Joshi, Abhijeet R., Barham, Mohammed, Neiss, Wolfram F. and Lehmann, Helmar C. (2018). Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy. Mol. Neurobiol., 55 (2). S. 1227 - 1236. TOTOWA: HUMANA PRESS INC. ISSN 1559-1182

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bobylev, Ilja UNSPECIFIED UNSPECIFIED UNSPECIFIED Joshi, Abhijeet R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Barham, Mohammed UNSPECIFIED UNSPECIFIED UNSPECIFIED Neiss, Wolfram F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmann, Helmar C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-197549
DOI:	10.1007/s12035-016-0364-7
Journal or Publication Title:	Mol. Neurobiol.
Volume:	55
Number:	2
Page Range:	S. 1227 - 1236
Date:	2018
Publisher:	HUMANA PRESS INC
Place of Publication:	TOTOWA
ISSN:	1559-1182
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN DRP1; INTRACELLULAR CALCIUM; PERIPHERAL NEUROPATHY; NEUROBLASTOMA-CELLS; HUNTINGTONS-DISEASE; SENSORY NEUROPATHY; ALZHEIMERS-DISEASE; GANGLION NEURONS; AXONAL-TRANSPORT; DNA ADDUCTS Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19754