Peripheral neuropathy is a prevalent complication of diabetes and prediabetes characterized by distal-to-proximal peripheral nerve damage. Dyslipidemia is a contributory factor that underlies neuropathy development in type 2 diabetes and prediabetes. However, the molecular pathways that underlie sensory neuron dysfunction in peripheral neuropathy associated with diabetes and prediabetes are unknown. Our recent lipidomic and transcriptomic analyses identified altered metabolism of polyunsaturated omega-6 fatty acid linoleic acid in the peripheral nerves of prediabetic mice with neuropathy. However, the molecular effect of linoleic acid on sensory neurons remains unknown. Since sensory dorsal root ganglion (DRG) neurons are dependent on trafficking mechanisms to transport healthy mitochondria throughout the length of the axon, we evaluated the effect of linoleic acid on axonal mitochondrial trafficking and function in DRG neurons. Primary DRG neurons from adult C57BL/6J mice were treated with physiological concentrations of linoleic acid ranging from 31.25-250 µM for 24 hours. Following treatment, we evaluated the effect of linoleic acid treatments on mitochondrial trafficking, mitochondrial membrane potential, ATP level, and apoptosis in DRG neurons. Interestingly, all concentrations of linoleic acid ranging from 31.25-250 µM preserved mitochondrial membrane potential and ATP level in DRG neurons. In line with these results, linoleic acid treatments did not stimulate neuronal apoptosis. However, physiological diabetic concentrations of 250 µM linoleic acid significantly impaired mitochondrial trafficking in the axon of DRG neurons. Overall, these results suggest that elevated levels of linoleic acid impair axonal mitochondrial trafficking without effecting mitochondrial function, and that defects in mitochondrial trafficking of sensory neurons may contribute to neuropathy pathogenesis in diabetes and prediabetes.
A. Rumora: None. G. LoGrasso: None. J.D. McGrath: None. S.I. Lentz: None. E.L. Feldman: Consultant; Self; Novartis Pharmaceuticals Corporation.
American Diabetes Association (7-12-BS-045 to E.L.F.); National Institutes of Health (1R24082841, 1DP3DK094292); National Institute of Diabetes and Digestive and Kidney Diseases (T32DK101357, F32DK112642, K99DK119366, P30DK020572); NeuroNetwork for Emerging Therapies; A. Alfred Taubman Medical Research Institute