Ciliary neurotrophic factor reverses aberrant mitochondrial bioenergetics through the JAK/STAT pathway in cultured sensory neurons derived from streptozotocin-induced diabetic rodents
| Autor: | Nigel A. Calcutt, Dwane Morrow, Paul Fernyhough, Eli Akude, Subir K. Roy Chowdhury, Ali Saleh, Lori Tessler, Darrell R. Smith |
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| Rok vydání: | 2014 |
| Předmět: |
Male
STAT3 Transcription Factor Neurite Sensory Receptor Cells Mitochondrion Biology Ciliary neurotrophic factor Diabetes Mellitus Experimental Rats Sprague-Dawley Cellular and Molecular Neuroscience Mice medicine Animals Ciliary Neurotrophic Factor Axon Inner mitochondrial membrane STAT3 Cells Cultured Janus Kinases JAK-STAT signaling pathway Cell Biology General Medicine Sensory neuron Cell biology Mitochondria Rats Mice Inbred C57BL medicine.anatomical_structure nervous system biology.protein Energy Metabolism Neuroscience Signal Transduction |
| Zdroj: | Cellular and molecular neurobiology. 34(5) |
| ISSN: | 1573-6830 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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