Ciliary Neurotrophic Factor Reverses Aberrant Mitochondrial Bioenergetics
Through the JAK/STAT Pathway in Cultured Sensory Neurons Derived from
Streptozotocin-Induced Diabetic Rodents.
Authors Chowdhury SR, Saleh A, Akude E, Smith DR, Morrow D, Tessler L, Calcutt NA,
Fernyhough P
Submitted By Submitted Externally on 4/15/2014
Status Published
Journal Cellular and molecular neurobiology
Year 2014
Date Published 3/30/2014
Volume : Pages 34 : 643 - 649
PubMed Reference 24682898
Abstract Mitochondrial dysfunction occurs in sensory neurons and contributes to diabetic
neuropathy. Ciliary neurotrophic factor (CNTF) stimulates axon regeneration in
type 1 diabetic rodents and prevents deficits in axonal caliber, nerve
conduction, and thermal sensation. We tested the hypothesis that CNTF enhances
sensory neuron function in diabetes through JAK/STAT (Janus kinase/signal
transducers and activators of transcription) signaling to normalize impaired
mitochondrial bioenergetics. The effect of CNTF on gene expression and neurite
outgrowth of cultured adult dorsal root ganglia (DRG) sensory neurons derived
from control and streptozotocin (STZ)-induced diabetic rodents was quantified.
Polarization status and bioenergetics profile of mitochondria from cultured
sensory neurons were determined. CNTF treatment prevented reduced STAT3
phosphorylation (Tyr 705) in DRG of STZ-diabetic mice and also enhanced STAT3
phosphorylation in rat DRG cultures. CNTF normalized polarization status of the
mitochondrial inner membrane and corrected the aberrant oligomycin-induced
mitochondrial hyperpolarization in axons of diabetic neurons. The mitochondrial
bioenergetics profile demonstrated that spare respiratory capacity and
respiratory control ratio were significantly depressed in sensory neurons
cultured from STZ-diabetic rats and were corrected by acute CNTF treatment. The
positive effects of CNTF on neuronal mitochondrial function were significantly
inhibited by the specific JAK inhibitor, AG490. Neurite outgrowth of sensory
neurons from age-matched control and STZ-induced diabetic rats was elevated by
CNTF and blocked by AG490. We propose that CNTF's ability to enhance axon
regeneration and protect from fiber degeneration in diabetes is associated with
its targeting of mitochondrial function and improvement of cellular
bioenergetics, in part, through JAK/STAT signaling.

Investigators with authorship
Nigel CalcuttUniversity of California San Diego