Connexin 43 mediated mitochondrial transfer prevents cisplatin induced sensory neurodegeneration.

Abstract

Platinum based chemotherapeutics including cisplatin are front-line treatments for paediatric and adult cancer. Despite advancements in medical interventions, chemotherapy-induced peripheral sensory neuropathy is a common adverse health related complication that can persist for the long-term and impacts upon an individuals quality of life. Recently, the causes of chemotherapy induced sensory neurodegeneration has been linked to sensory neuronal mitochondrial dysfunction. Here this study investigated how monocytic mitochondria donation to recipient cisplatin damaged dorsal root ganglia (DRG) sensory neurons prevented platinum-based chemotherapy-induced sensory neurotoxicity. Neuronal cell line, SH-SY5Y, or mouse DRG sensory neurons were treated with either vehicle or cisplatin, and co-cultured with mitotracker-labelled THP1 monocytes. Cisplatin induced dysmorphic mitochondria and diminished oxidative phosphorylation dependent energy production in cisplatin treated dorsal root ganglia sensory neurons. DRG sensory neurons exposed to cisplatin were recipients of monocyte mitochondria indicated by increased intracellular mitotracker fluorescent labelling. Mitochondrial transfer to sensory neurons was neuroprotective, preventing neurite loss and sensory neuronal apoptosis. Vehicle treated DRG sensory neurons did not demonstrate significant mitochondrial uptake. Furthermore, cisplatin induced mitochondrial transfer was prevented by pharmacological inhibition of gap junction protein, connexin 43. Connexin 43 inhibition led to reduced neuroprotective capacity via mitochondrial transfer. These findings demonstrate that monocytic mitochondria transfer to DRG sensory neurons damaged by cisplatin, is dependent upon gap junction intercellular communication to promote sensory neuronal survival. This novel process in sensory neuronal protection is a potential novel therapeutic intervention for alleviating neuropathic pain in individuals treated for cancer.