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.