Diabetic neuropathy (DN) is a highly prevalent complication of type 2 diabetes that is associated with dyslipidemia and causes length-dependent sensory nerve damage in the lower extremities. The primary sensory neurons, dorsal root ganglion (DRG) neurons, extend bundles of axons into the peripheral nerves and transmit sensory information from the limbs. These neurons require a constant supply of mitochondrial derived energy maintained by trafficking of the mitochondria throughout the length of the DRG axon. We have shown that dyslipidemia-associated saturated fatty acid (FA) palmitate impairs mitochondrial trafficking whereas unsaturated FA oleate prevents this impairment. In the current study, we assessed whether FAs alter trafficking of synaptic vesicles in DRG axons to determine whether palmitate impairs mitochondrial trafficking specifically or global organellar transport. Primary DRG neurons were treated with physiological concentrations of FAs ranging from 31.25-250 µM saturated FA palmitate, unsaturated FA oleate, and oleate/palmitate mixtures. Mitochondria and synaptic vesicles showed a significant dose-dependent reduction in motility with increasing concentrations of saturated FA palmitate. However, mitochondria and synaptic vesicles retained motility with treatments of unsaturated FA oleate compared to the controls. Similarly, palmitate induced a trending decrease in velocity of bi-directional motile mitochondria and synaptic vesicles, whereas oleate treatments did not alter mitochondrial and synaptic vesicle velocity. Finally, co-incubation of oleate prevents palmitate-induced inhibition of mitochondrial and synaptic vesicle trafficking. These results suggest that high concentrations of saturated FAs lead to the dysfunction of global organellar transport throughout the DRG axon associated with the development and progression of DN.

Disclosure

G. LoGrasso: None. A. Rumora: None. J.A. Haidar: None. S.I. Lentz: None. E.L. Feldman: None.

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