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High dietary fat consumption impairs axonal mitochondrial function in vivo

Sajic, M; Rumora, AE; Kanhai, AA; Dentoni, G; Varatharajah, S; Casey, C; Brown, RDR; ... Smith, KJ; + view all (2021) High dietary fat consumption impairs axonal mitochondrial function in vivo. Journal of Neuroscience , 41 (19) pp. 4321-4334. 10.1523/JNEUROSCI.1852-20.2021. Green open access

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Abstract

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia in vitro demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis in vivo. We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca^{2+} levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca^{2+} levels and impairs impulse conduction within the saphenous nerve in prediabetic PN.

Type: Article
Title: High dietary fat consumption impairs axonal mitochondrial function in vivo
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.1852-20.2021
Publisher version: https://doi.org/10.1523/JNEUROSCI.1852-20.2021
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: dorsal root ganglion, high-fat, diet, mitochondria, mouse model, peripheral neuropathy, sensory neuron
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neuroinflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10125876
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