Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Abstract

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG) neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased reactive oxygen species generation, ATP level reduction, calcium release and mitochondrial swelling. Cisplatin and oxaliplatin form adducts with mitochondrial DNA producing inhibition of replication, disruption of transcription and morphological abnormalities within mitochondria in DRG neurons, leading to a gradual energy failure. Bortezomib is able to modify mitochondrial calcium homeostasis and mitochondrial respiratory chain. Moreover, the expression of a certain number of genes, including those controlling mitochondrial functions, was altered in patients with bortezomib-induced peripheral neuropathy.

Keywords: Chemotherapy compounds; mitochondria; mitotoxicity; neuropathic pain; peripheral neurotoxicity.

Figure 1

Graphical summary of paclitaxel-induced mechanisms of neurotoxicity: principal effects on mitochondrion (nDNA = nuclear DNA, mPTP = mitochondrial Permeability Transition Pore, Cyt c = Cytochrome C, Ca²⁺ = calcium, ROS = Reactive Oxygen Species).

Figure 2

Graphical summary of cisplatin-induced mechanisms of neurotoxicity: principal effects on mitochondrion (nDNA = nuclear DNA, Pt = platinum, mDNA = mitochondrial DNA, Cyt c = Cytochrome C, ROS = Reactive Oxygen Species).

Figure 3

Graphical summary of oxaliplatin-induced mechanisms of neurotoxicity: principal effects on mitochondrion (nDNA = nuclear DNA, Pt = platinum, mDNA = mitochondrial DNA, Cyt c = Cytochrome C, ROS = Reactive Oxygen Species, mPTP = mitochondrial Permeability Transition Pore).

Figure 4

Graphical summary of vincristine-induced mechanisms of neurotoxicity: principal effects on mitochondrion (nDNA = nuclear DNA, ROS = Reactive Oxygen Species, Ca²⁺ = calcium).

Figure 5

Graphical summary of bortezomib-induced mechanisms of neurotoxicity: principal effects on mitochondrion (nDNA = nuclear DNA, ROS = Reactive Oxygen Species, Ca ²⁺ = calcium, Na⁺ = sodium, K⁺ = potassium).