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.

N-acetylcysteine versus progesterone on the cisplatin-induced peripheral neurotoxicity

“…The mechanisms underlying CIPN are incompletely understood [7]. The first possible studied mechanism was the reduction in the tissue antioxidants (SOD and GSH) and the increase in the tissue oxidants (MDA), which were observed in the cisplatin-treated group.…”

A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy

“…Mitochondrial dysfunction is commonly observed in CIPN (Figure 1 ). Abnormal mitochondrial morphology including swelling, vacuolation, enlargement, and loss of cristae structure have been observed in peripheral nerve axons (Flatters and Bennett, 2006 ; Xiao et al, 2012 ; Zheng et al, 2012 ; Bobylev et al, 2017 ), but not in the surrounding Schwann cells (Xiao et al, 2012 ) in several CIPN animal models. Potential causes of altered mitochondria include paclitaxel-induced depletion of mRNAs encoding mitochondrial fission/fusion machinery in distal axons (Bobylev et al, 2015 ).…”

“…Potential causes of altered mitochondria include paclitaxel-induced depletion of mRNAs encoding mitochondrial fission/fusion machinery in distal axons (Bobylev et al, 2015 ). Mitochondria dynamics may be altered in cisplatin-treated animals due to decreased level of mitochondrial fusion protein MFN2 in distal axon segments (Bobylev et al, 2017 ). Moreover, increased mitochondrial fragmentation, as well as decreased mitochondrial fission/fusion dynamics and motility, occur rapidly in vincristine-treated DRG cultures and precede axon degeneration (Berbusse et al, 2016 ).…”

Platinum-induced neurotoxicity: A review of possible mechanisms

“…Some studies have demonstrated that cisplatin can alter the expression of mitochondrial fusion and fission proteins in peripheral nerves[ 25 ]. These proteins regulate mitochondrial shape, size, and number.…”

“…These proteins regulate mitochondrial shape, size, and number. Bobylev et al[ 25 ] detected a significant decrease in the mitochondrial fusion protein mitofusin 2 expression levels in DRG and tibial nerves of cisplatin-treated mice, resulting in mitochondrial swelling and vacuolization.…”