Disorders of mitochondrial dynamics in peripheral neuropathy: Clues from hereditary neuropathy and diabetes

Abstract

Peripheral neuropathy is a common and debilitating complication of diabetes and prediabetes. Recent clinical studies have identified an association between the development of neuropathy and dyslipidemia in prediabetic and diabetic patients. Despite the prevalence of this complication, studies identifying molecular mechanisms that underlie neuropathy progression in prediabetes or diabetes are limited. However, dysfunctional mitochondrial pathways in hereditary neuropathy provide feasible molecular targets for assessing mitochondrial dysfunction in neuropathy associated with prediabetes or diabetes. Recent studies suggest that elevated levels of dietary saturated fatty acids (SFAs) associated with dyslipidemia impair mitochondrial dynamics in sensory neurons by inducing mitochondrial depolarization, compromising mitochondrial bioenergetics, and impairing axonal mitochondrial transport. This causes lower neuronal ATP and apoptosis. Conversely, monounsaturated fatty acids (MUFAs) restore nerve and sensory mitochondrial function. Understanding the mitochondrial pathways that contribute to neuropathy progression in prediabetes and diabetes may provide therapeutic targets for the treatment of this debilitating complication.

Keywords: Bioenergetics; Charcot-Marie-Tooth disease; Diabetes; Fission; Fusion; Hereditary neuropathy; Mitochondria; Mitochondrial associated membranes; Mitochondrial trafficking; Prediabetes.

Fig. 1

Schematic of mitochondrial fission and fusion dynamics. Mitochondrial bioenergetics are regulated by mitochondrial fission and fusion events. Mitochondrial fusion events retain mitochondrial bioenergetic function, MMP, ATP production, and decrease ROS generation and apoptosis. Conversely, mitochondrial fission leads to mitochondrial depolarization which impairs mitochondrial bioenergetic function and decreases ATP production. Compromised bioenergetics lead to ROS production triggering apoptosis.

Fig. 2

A dietary switch from a SFA-rich HFD to a MUFA-rich HFD restores nerve function in a murine model of prediabetes and neuropathy. A) Mice fed a SFA-rich HFD develop robust neuropathy phenotypes including a decrease in sensory and motor nerve conduction velocity and a reduction in intraepidermal nerve fiber density. In line with these results, cultured DRG neurons treated with SFAs exhibit a decrease in axonal mitochondrial trafficking and MMP. These mitochondrial changes are associated with apoptosis and a reduction in neuronal ATP level. B) Changing mice from a SFA-rich diet to a MUFA-rich diet restores both nerve and mitochondrial function.

Fig. 3

Dyslipidemia decreases mitochondrial function in DRG neurons. (A) LCSFA palmitate induces a loss of MMP through mitochondrial depolarization. Mitochondria labeled with mito-GFP are stained with MMP-dependent stain TMRM. Axonal mitochondria maintain MMP in the bovine serum albumin vehicle control and appear yellow in an overlay of both signals. Palmitate-treated cells exhibit a loss in TMRM staining due to mitochondrial depolarization. (B) Palmitate impairs mitochondrial bioenergetics through mitochondrial depolarization by increasing basal respiration and ATP turn over which leads to a decrease in coupling efficiency and increased proton leak from the electron transport chain. Bioenergetics bar graphs included with permission from Rumora, A.E., Lentz, S.I., Hinder, L.M., Jackson, S.W., Valesano, A., Levinson, G.E., and Feldman, E.L. (2018). Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons. Faseb j 32, 195–207. Mitochondrial depolarization figures adapted with permission from Rumora, A.E., LoGrasso, G., Haidar, J.A., Dolkowski, J.J., Lentz, S.I., and Feldman, E.L. (2019). Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons. J Lipid Res 60, 58–70.

Fig. 4

SFAs impair axonal mitochondrial transport in DRG neurons. (A) A kymograph analysis is used to record mitochondrial movement from 0–150 seconds using live-cell confocal microscopy. Straight lines indicate non-motile mitochondria. Elevated levels of exogenous short and medium chain SFAs laurate (B) and myristate (C) did not impact the number of motile mitochondrial in the axon of sensory DRG neurons. LCSFAs associated with T2D and prediabetes such as palmitate (D) and stearate (E) induce a dose-dependent decrease in the percentage of motile mitochondria in the axon of sensory DRG neurons. (F) MUFA oleate had no effect on mitochondrial motility. (G) Mixtures of oleate and palmitate prevented palmitate-induced impairment of mitochondrial transport. SFA kymographs and bar graphs modified with permission from Rumora, A.E., LoGrasso, G., Haidar, J.A., Dolkowski, J.J., Lentz, S.I., and Feldman, E.L. (2019). Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons. J Lipid Res 60, 58–70. Permission to be obtained for MUFA kymographs and bar graphs from J. Neurosci upon release of paper in press.