Saturated Fatty Acids Alter Mitochondrial Trafficking in Dorsal Root Ganglion (DRG) Sensory Neurons

Abstract

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes that causes length-dependent degeneration of sensory nerves in the lower extremities. Hyperlipidemia, or an abnormally high concentration of fats or lipids, is a major risk factor for the development of neuropathy. The dysfunction of mitochondria in sensory neurons is a potential mechanism for this sensory loss associated with DPN. Mitochondria provide the main source of cellular energy vital for neuronal growth and function. Mitochondrial motility and distribution are altered under certain stress conditions. The current study investigates the effect of hyperlipidemia on mitochondrial trafficking in dorsal root ganglion (DRG) sensory neurons. Primary culture of DRG neurons were treated separately with saturated fatty acids palmitate, stearate, and unsaturated fatty acid oleate at increasing concentrations. Additionally, neuronal cultures were treated with common dietary fatty acids palmitate and oleate in combination, with increasing molar ratios of the latter. Live cell imaging was performed to quantify the percentage of motile mitochondria, percentage of anterograde and retrograde-moving mitochondria, as well as their respective velocities. Overall, saturated fatty acids oleate and stearate impaired mitochondrial trafficking in sensory neurons, leading to a reduction of mitochondrial motility and velocity, whereas unsaturated fatty acid oleate did not impair mitochondrial trafficking. Also, coincubation with oleate successfully blocked the palmitate-induced neuronal degeneration, preventing impairment of mitochondrial trafficking. Understanding mitochondrial dysfunction can lead to a better understanding of the time course and progression of DPN for the eventual development of reliable treatments and therapeutics.