Diabetic neuropathy (DN) is a common complication of type 2 diabetes characterized by peripheral nerve damage and sensory loss. Dorsal root ganglion (DRG) sensory neurons require axonal mitochondrial transport to produce axonal ATP for neuronal function. In DN, DRG neurons exhibit axonal mitochondrial dysfunction and bioenergetic failure. A correlation between DN progression and dyslipidemia suggests that increased plasma saturated fatty acids (FAs) and decreased unsaturated FAs may play a role in the progression of DN. In this study, we evaluated the effect of saturated FA palmitate and monounsaturated FA oleate on mitochondrial trafficking and mitochondrial function in DRG neurons. Primary DRG neurons were treated with physiological concentrations of palmitate, oleate, and oleate/palmitate mixtures. The impact of these treatments was assessed by measuring mitochondrial motility and mitochondrial membrane depolarization using TMRM staining. Treatment with 62.5 μM to 250 μM palmitate induced a significant and dose-dependent decrease in axonal mitochondrial transport whereas oleate treatments from 31.25 to 250 μM did not alter the percentage of motile mitochondria. Palmitate treatments also resulted in a reduction of mitochondrial membrane potential in DRG neurons treated with 125 to 250 μM palmitate. Conversely, DRG neurons treated with 125 to 250 μM oleate maintained their mitochondrial membrane potential. Based on the differential effects of oleate and palmitate, we next evaluated whether oleate supplementation could prevent palmitate-induced inhibition of mitochondrial trafficking. Mixtures of oleate/palmitate at 1:1 or 2:1 molar ratios prevented palmitate-induced decreases in mitochondrial trafficking and mitochondrial membrane depolarization. These results indicate that monounsaturated FAs prevent saturated FA induced mitochondrial dysfunction in DRG neurons associated with dyslipidemia and DN.
A. Rumora: None. G. LoGrasso: None. J.A. Haidar: None. J. Dolkowski: None. S.I. Lentz: None. E.L. Feldman: None.