Long-Chain Acyl Coenzyme A Synthetase 1 Overexpression in Primary Cultured Schwann Cells Prevents Long Chain Fatty Acid-Induced Oxidative Stress and Mitochondrial Dysfunction

Abstract

Aims: High circulating long chain fatty acids (LCFAs) are implicated in diabetic neuropathy (DN) development. Expression of the long-chain acyl-CoA synthetase 1 (Acsl1) gene, a gene required for LCFA metabolic activation, is altered in human and mouse diabetic peripheral nerve. We assessed the significance of Acsl1 upregulation in primary cultured Schwann cells. Results: Acsl1 overexpression prevented oxidative stress (nitrotyrosine; hydroxyoctadecadienoic acids [HODEs]) and attenuated cellular injury (TUNEL) in Schwann cells following 12 h exposure to LCFAs (palmitate, linoleate, and oleate, 100 lM). Acsl1 overexpression potentiated the observed increase in medium to long-chain acyl-carnitines following 12 h LCFA exposure. Data are consistent with increased mitochondrial LCFA uptake, largely directed to incomplete beta-oxidation. LCFAs uncoupled mitochondrial oxygen consumption from ATP production. Acsl1 overexpression corrected mitochondrial dysfunction, increasing coupling efficiency and decreasing proton leak. Innovation: Schwann cell mitochondrial function is critical for peripheral nerve function, but research on Schwann cell mitochondrial dysfunction in response to hyperlipidemia is minimal. We demonstrate that high levels of a physiologically relevant mixture of LCFAs induce Schwann cell injury, but that improved mitochondrial uptake and metabolism attenuate this lipotoxicity. Conclusion: Acsl1 overexpression improves Schwann cell function and survival following high LCFA exposure in vitro; however, the observed endogenous Acsl1 upregulation in peripheral nerve in response to diabetes is not sufficient to prevent the development of DN in murine models of DN. Therefore, targeted improvement in Schwann cell metabolic disposal of LCFAs may improve DN phenotypes. Antioxid. Redox Signal. 21, 588-600.

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

“…Interestingly, increases in caspase 3/7 activity were only observed at higher concentrations of 187.5-250 M palmitate and stearate, despite the fact that the 62.5 M palmitate and stearate treatments impaired mitochondrial trafficking and induced mitochondrial depolarization. These results indicate that mitochondrial depolarization and impaired trafficking likely precede neuronal apoptosis (14,16,60). We acknowledge that the concentration of LCSFAs required to enhance apoptosis could be due to inherent metabolic differences in 50B11 cells, a transformed DRG cell line (42), compared with primary DRG neurons; however, the current data support our contention that abnormal mitochondrial trafficking and mitochondrial depolarization correlate with increased DRG neuronal apoptosis.…”

New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain

“…Similar to adipocytes, SCs transport long chain fatty acids (LCFAs) from the extracellular space into the SC cytoplasm in T2D, and cultured SCs increase the expression of carnitine palmitoyltransferase I (CPT1) in response to LCFA treatment (Hinder et al, 2014). CPT1 transports the LCFA acyl-CoA esters, along with the carnitine shuttle and CPT2, to the mitochondrial matrix to undergo β-oxidation, with repeat cleavage of 2 carbons to form acetyl-CoA with each cycle.…”

Neurological consequences of obesity

“…Excess LCFA promote increased Schwann cell mitochondrial β-oxidation 93,94 that is coincident with polyneuropathy. 95,96 Products of LCFA metabolism, LC-acylcarnitines, accumulate in peripheral nerves of mice 94 and these bioactive lipids are associated with Schwann cell dysfunction, 93 axonal degeneration, 94 and polyneuropathy. Accumulation of LCFA or LC-acylcarnitines in non-obesity-mediated diseases affecting mitochondrial β-oxidation also results in polyneuropathy, strengthening the association between aberrant lipid metabolism and PNS dysfunction.…”