Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons

Rumora, Amy E.; Lentz, Stephen I.; Hinder, Lucy M.; Jackson, Samuel; Valesano, Andrew L; Levinson, Gideon E.; Feldman, Eva L.

doi:10.1096/fj.201700206r

Cited by 72 publications

(86 citation statements)

References 78 publications

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“…DRG neuron preparation for confocal imaging included dissection of adult C57Bl/6J mice, dissociation of extracted DRGs, and culture of DRG neurons per our previously published protocols (16,(34)(35)(36). All animal work protocols adhered to the state, federal, and University of Michigan guidelines accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International.…”

Section: Primary Drg Neuron Culturesmentioning

confidence: 99%

“…Subsequent to a 30 min incubation in 2 mg/ml collagenase (Millipore-Sigma, Billerica, MA), DRGs were dissociated into a single-cell suspension by consecutive trituration with a Pasteur pipet and a fire-polished glass pipet in heat-inactivated BSA. Dissociated neurons were resuspended in primary DRG neuron treatment medium (TM) [50% F-12K (Cell Gro; Corning, Manassas, VA) and 50% DMEM (Cell Gro; Corning), 1:100 dilution of Nb + , 1,000 U/ml penicillin/ streptomycin/neomycin (Thermo Fisher Scientific, Waltham, MA), and 7.2 M aphidicolin (Millipore-Sigma)] supplemented with 1× B27 and 0.4 M l-glutamine (16). Neurons were transfected with 3.75 l/ml CellLight mitochondria-GFP (mito-GFP BacMam 2.0, Thermo Fisher Scientific) prior to plating on 4-well 25 g/ml laminin-coated (Millipore-Sigma) Nuc Lab-Tek chambered coverglass imaging plates (Thermo Fisher Scientific).…”

Section: Primary Drg Neuron Culturesmentioning

confidence: 99%

“…Neurons were transfected with 3.75 l/ml CellLight mitochondria-GFP (mito-GFP BacMam 2.0, Thermo Fisher Scientific) prior to plating on 4-well 25 g/ml laminin-coated (Millipore-Sigma) Nuc Lab-Tek chambered coverglass imaging plates (Thermo Fisher Scientific). DRG neurons adhered after 24 h, and medium was replaced with primary DRG neuron feed medium (TM containing 1× B27) (16) for another 24 h. Within 48 h after plating, DRG neurons extended axons and were treated with SFAs ranging in hydrocarbon chain lengths from C12:0C18:0.…”

Section: Primary Drg Neuron Culturesmentioning

confidence: 99%

“…DRG neuron cultures were treated for 24 h with 31.25250 M laurate (C12:0), myristate (C14:0), palmitate (C16:0), or stearate (C18:0). All SFAs were conjugated to FA-free BSA (Thermo Fisher Scientific) as described previously (16) and diluted to final concentration(s) in TM. A TM control was used to establish the basal level of mitochondrial trafficking in DRG neurons.…”

Section: Sfa Treatmentsmentioning

confidence: 99%

“…Mitochondrial trafficking mechanisms and mitochondrial function are regulated by a complex network of both posttranslational cues and the metabolic state to maintain axonal energy homeostasis (29)(30)(31)(32)(33). Interestingly, our recent studies indicate that mitochondrial trafficking mechanisms are tightly regulated by the LCSFA palmitate, which impairs mitochondrial transport in DRG neurons and impairs mitochondrial function (16). In this study, we evaluated the metabolic effects of SFA hydrocarbon chain length on mitochondrial axonal transport, mitochondrial function, and apoptosis in DRG sensory neurons.…”

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confidence: 97%

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

Rumora

Lograsso

Haidar

et al. 2019

Journal of Lipid Research

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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

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Section: Primary Drg Neuron Culturesmentioning

confidence: 99%

Section: Primary Drg Neuron Culturesmentioning

confidence: 99%

Section: Primary Drg Neuron Culturesmentioning

confidence: 99%

Section: Sfa Treatmentsmentioning

confidence: 99%

mentioning

confidence: 97%

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

Rumora

Lograsso

Haidar

et al. 2019

Journal of Lipid Research

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Plasma lipid metabolites associate with diabetic polyneuropathy in a cohort with type 2 diabetes

Rumora

Guo

Alakwaa

et al. 2021

Ann Clin Transl Neurol

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Objective: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown. Methods: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION-Denmark) with and without diabetic polyneuropathy versus lean control participants. Results: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids. Interpretation: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism.

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Functional consequences of brain exposure to saturated fatty acids: From energy metabolism and insulin resistance to neuronal damage

Sánchez-Alegría

Arias

2022

Endocrino Diabet & Metabol

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Introduction Saturated fatty acids (FAs) are the main component of high‐fat diets (HFDs), and high consumption has been associated with the development of insulin resistance, endoplasmic reticulum stress and mitochondrial dysfunction in neuronal cells. In particular, the reduction in neuronal insulin signaling seems to underlie the development of cognitive impairments and has been considered a risk factor for Alzheimer's disease (AD). Methods This review summarized and critically analyzed the research that has impacted the field of saturated FA metabolism in neurons. Results We reviewed the mechanisms for free FA transport from the systemic circulation to the brain and how they impact neuronal metabolism. Finally, we focused on the molecular and the physiopathological consequences of brain exposure to the most abundant FA in the HFD, palmitic acid (PA). Conclusion Understanding the mechanisms that lead to metabolic alterations in neurons induced by saturated FAs could help to develop several strategies for the prevention and treatment of cognitive impairment associated with insulin resistance, metabolic syndrome, or type II diabetes.

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Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons

Cited by 72 publications

References 78 publications

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

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

Plasma lipid metabolites associate with diabetic polyneuropathy in a cohort with type 2 diabetes

Functional consequences of brain exposure to saturated fatty acids: From energy metabolism and insulin resistance to neuronal damage

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