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Ciliary Neurotrophic Factor Reverses Aberrant Mitochondrial Bioenergetics Through the JAK/STAT Pathway in Cultured Sensory Neurons Derived from Streptozotocin-Induced Diabetic Rodents

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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.

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Acknowledgments

Drs. S. Roy Chowdhury and A. Saleh were supported by grants to P. Fernyhough from Canadian Institutes for Health Research (CIHR; Grant # MOP-84214) and Juvenile Diabetes Research Foundation (Grant # 1-2008-193). Dr. E. Akude was supported by a Grant from the National Science and Engineering Research Council (Grant # 3311686-06) to P. Fernyhough and subsequently a postgraduate scholarship from the Manitoba Health Research Council. Dr. Calcutt was supported by NIH Grant DK057629. The authors thank St. Boniface Research for funding support, Dr. G. Glazner, University of Manitoba and St. Boniface Hospital Research Centre, for permitting access to the Carl Zeiss LSM 510 microscope and Ms. Katie Frizzi for expert technical assistance.

Conflict of interest

The authors, Subir Roy Chowdhury, Ali Saleh, Eli Akude, Darrell Smith, Dwane Morrow, Lori Tessler, Nigel Calcutt and Paul Fernyhough state that they have no financial relationships with the organizations that sponsored this research.

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Authors and Affiliations

  1. Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, R4046 – 351 Taché Ave, Winnipeg, MB, R2H 2A6, Canada

    Subir Roy Chowdhury, Ali Saleh, Eli Akude, Darrell R. Smith, Dwane Morrow, Lori Tessler & Paul Fernyhough

  2. Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, MB, Canada

    Paul Fernyhough

  3. Department of Pathology, UCSD, La Jolla, CA, USA

    Nigel A. Calcutt

Authors
  1. Subir Roy Chowdhury
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  2. Ali Saleh
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  3. Eli Akude
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  4. Darrell R. Smith
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  5. Dwane Morrow
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  6. Lori Tessler
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  7. Nigel A. Calcutt
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  8. Paul Fernyhough
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Corresponding author

Correspondence to Paul Fernyhough.

Additional information

Subir Roy Chowdhury and Ali Saleh have contributed equally to this work.

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10571_2014_54_MOESM1_ESM.tiff

Supplementary Figure 1. CNTF activates JAK-STAT signaling pathways in cultured sensory neurons. In (a) shows Western blots of samples from normal rat DRG neurons treated for 1 hr with AG490 (JAK/STAT inhibitor) at 10 μM in the presence of low dose of neurotrophic factors and then stimulated with CNTF (10 ng/ml) for 30 min: phosphorylated-STAT3 (P-STAT3) on Tyr-705, total STAT3 (T-STAT3) and total ERK (T-ERK). (b) is graphed data for P-STAT3 expression normalized against T-ERK. In (c) graphed data for P-STAT3 expression normalized against T-STAT3 (from blots in (a)). Values are means ± SEM (n = 3 replicates). *p < 0.05 vs other groups (one- way ANOVA).

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Chowdhury, S.R., Saleh, A., Akude, E. et al. Ciliary Neurotrophic Factor Reverses Aberrant Mitochondrial Bioenergetics Through the JAK/STAT Pathway in Cultured Sensory Neurons Derived from Streptozotocin-Induced Diabetic Rodents. Cell Mol Neurobiol 34, 643–649 (2014). https://doi.org/10.1007/s10571-014-0054-9

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  • DOI: https://doi.org/10.1007/s10571-014-0054-9

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