Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons

Abstract

This article is available online at http://www.jlr.org experience a loss of sensation that occurs in a stockingand-glove distribution and has a severe impact on the individual's quality of life and societal productivity (3-7). The progressive loss of sensory function results from distal-toproximal peripheral nerve damage and dysfunction of sensory neurons. Although the pathogenesis of DPN is not fully understood, recent studies indicate that DPN pathogenesis is directly linked to a continuum of metabolic factors associated with dyslipidemia (8-10).Plasma concentrations of free saturated FAs (SFAs) are commonly elevated in T2D (11). In general, SFAs are classified as inducers of lipotoxicity (12, 13), mitochondrial dysfunction (14-17), and apoptosis (17); however, recent evidence indicates that hydrocarbon chain length of SFAs defines the level of intracellular lipotoxicity (18,19). Moreover, the Western diet, characterized by increased intake of foods with high levels of long-chain SFAs (LCSFAs), including myristate (C14:0), palmitate (C16:0), and stearate (C18:0), and low levels of beneficial medium-chain SFAs (MCSFAs), such as laurate (C12:0) (20-22), is a driving factor in the onset of dyslipidemia and T2D (23). MCSFAs are reported to prevent lipotoxicity and increase mitochondrial energy production (18,24,25). Likewise, equimolar caloric intake of MCSFAs and LCSFAs increases mitochondrial energy expenditure and leads to oxidative metabolic pathways as opposed to the metabolic dysfunction triggered by LCSFAs (24,26). SFAs are also directed to mitochondrial oxidative pathways through hydrocarbon chain length-dependent mechanisms; LCSFAs are targeted into the mitochondrial matrix for -oxidation through a transport system consisting of palmitoyltransferases (18,24,27), whereas MCSFAs are transported independently into the mitochondria, allowing for more efficient modulation of mitochondrial energy production (18,24). Hence, chain length of SFAs plays a critical role in regulating mitochondrial Abstract Dyslipidemia associated with T2D leads to diabetic neuropathy, a complication characterized by sensory neuronal dysfunction and peripheral nerve damage. Sensory dorsal root ganglion (DRG) neurons are dependent on axonal mitochondrial energy production facilitated by mitochondrial transport mechanisms that distribute mitochondria throughout the axon. Because long-chain saturated FAs (SFAs) damage DRG neurons and medium-chain SFAs are reported to improve neuronal function, we evaluated . Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons. J. Lipid Res. 2019. 60: 58-70. Supplementary key words diabetes • dyslipidemias • apoptosis • palmitate • stearate • laurate • myristate • mitochondrial depolarizationDiabetic peripheral neuropathy (DPN) is a common complication that affects up to 30% of patients with prediabetes and 50% of T2D patients (1, 2). Patients with DPN

The Divergent Roles of Dietary Saturated and Monounsaturated Fatty Acids on Nerve Function in Murine Models of Obesity

“…Primary DRG neuron cultures were used to evaluate the effect of oleate and palmitate fatty acid treatments on axonal mitochondrial transport, mitochondrial membrane potential (MMP) and lipid droplet formation. DRG neurons from adult 16-to 18-week-old male C57BL/6J mice (The Jackson Laboratory) were dissected and cultured as described in our previously published protocols (Vincent et al, 2007(Vincent et al, , 2009aRumora et al, 2018Rumora et al, , 2019. Briefly, intact DRG were incubated in 2 mg/ml collagenase (Millipore-Sigma) for 30 min at 37°C.…”

“…The DRG were then mechanically dissociated in heatinactivated bovine serum albumin (BSA) using repetitive trituration. DRG neurons were resuspended in treatment media (TM; 50% F-12K; Cell Gro, Corning) and 50% DMEM (Cell Gro, Corning), 1:100 dilution of Nb ϩ , 1000 U/ml penicillin/streptomycin/neomycin (ThermoFisher Scientific), 7.2 M aphidicolin (Millipore-Sigma), supplemented with 1ϫ B27 and 0.4 M L-glutamine (Rumora et al, 2018(Rumora et al, , 2019 and transfected with mitochondria-GFP by adding 3.75 l/ml CellLight mitochondria-GFP (mito-GFP BacMam 2.0, ThermoFisher Scientific). The DRG neurons were then plated on 4-well Nuc Lab-Tek chambered cover glass imaging plates (ThermoFisher Scientific) coated with 25 g/ml laminin (Millipore-Sigma).…”

“…The DRG neurons were then plated on 4-well Nuc Lab-Tek chambered cover glass imaging plates (ThermoFisher Scientific) coated with 25 g/ml laminin (Millipore-Sigma). After 24 h, the DRG neuron culture media was replaced with feed media composed of TM and 1ϫ B27 sup-plement for another 24 h allowing for DRG axon outgrowth (Rumora et al, , 2019.…”

“…This SFAinduced impairment of mitochondrial transport is accompanied by mitochondrial depolarization and impaired mitochondrial bioenergetics (Rumora et al, 2018). Dysfunctional bioenergetics lowers the level of intracellular ATP and initiates DRG apoptosis (Rumora et al, 2019). These studies indicate that lipotoxic SFAs impair mitochondrial function and play a critical role in peripheral neuropathy progression.…”

“…DRG neurons are dependent on mitochondrial ATP production throughout the axon and rely on mitochondrial transport mechanisms to distribute mitochondria for normal nerve function (Schwarz, 2013;Sheng, 2014). DRG neurons exposed to elevated levels of SFAs exhibit a decrease in motile axonal mitochondria (Rumora et al, 2018(Rumora et al, , 2019. This SFAinduced impairment of mitochondrial transport is accompanied by mitochondrial depolarization and impaired mitochondrial bioenergetics (Rumora et al, 2018).…”