Mitochondrial damage and “plugging” of transport selectively in myelinated, small-diameter axons are major early events in peripheral neuroinflammation

Sajic, Marija; Ida, Keila Kazue; Canning, Ryan; Gregson, N. A.; Duchen, Michael R.; Smith, Kenneth J.

doi:10.1186/s12974-018-1094-8

Cited by 15 publications

(12 citation statements)

References 52 publications

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“…The response to short-term HFD in young mice may represent a compensatory mechanism to counteract partial MMP loss and impaired energy production (Baqri et al, 2009), which may fail in old animals. In young mice, healthy polarized mitochondria are rapidly transported into areas of localized, experimentally induced saphenous nerve axon damage to avert local bioenergetics collapse (Sajic et al, 2018). The discrepancy between our in vitro and in vivo results perhaps reflects myelination state, which is absent in vitro but present around many saphenous axons in vivo (Ohno et al, 2011).…”

Section: Discussionmentioning

confidence: 65%

High Dietary Fat Consumption Impairs Axonal Mitochondrial FunctionIn Vivo

et al. 2021

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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 21 levels and increased mitochondrial lengthening and expression of PGC1a, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca 21 levels and impairs impulse conduction within the saphenous nerve in prediabetic PN.

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Section: Discussionmentioning

confidence: 65%

High Dietary Fat Consumption Impairs Axonal Mitochondrial FunctionIn Vivo

et al. 2021

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“…Hence, a future study could focus on determining how protecting the lesion site affects the activation of apoptotic pathways in spinal cord segments distant from the injury site. Dysfunctional mitochondria are also linked to neuroinflammation [39], and hence, protecting mitochondria could have reduced the inflammation-mediated damage to the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticles with antioxidant enzymes protect injured spinal cord from neuronal cell apoptosis by attenuating mitochondrial dysfunction

Andrabi

Yang

Gao

et al. 2020

Journal of Controlled Release

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In spinal cord injury (SCI), the initial damage leads to a rapidly escalating cascade of degenerative events, known as secondary injury. Loss of mitochondrial homeostasis after SCI, mediated primarily by oxidative stress, is considered to play a crucial role in the proliferation of secondary injury cascade. We hypothesized that effective exogenous delivery of antioxidant enzymessuperoxide dismutase (SOD) and catalase (CAT), encapsulated in biodegradable nanoparticles (nano-SOD/CAT) -at the lesion site would protect mitochondria from oxidative stress, and hence the spinal cord from secondary injury. Previously, in a rat contusion model of severe SCI, we demonstrated extravasation and retention of intravenously administered nanoparticles specifically at the lesion site. To test our hypothesis, a single dose of nano-SOD/CAT in saline was administered intravenously 6 h post-injury, and the spinal cords were analyzed one week posttreatment. Mitochondria isolated from the affected region of the spinal cord of nano-SOD/CAT treated animals demonstrated significantly reduced mitochondrial reactive oxygen species (ROS) activities, increased mitochondrial membrane potential, reduced calcium levels, and also higher adenosine triphosphate (ATP) production capacity than those isolated from the spinal cords of untreated control or SOD/CAT solution treated animals. Although the treatment did not achieve the same mitochondrial function as in the spinal cords of sham control animals, it significantly attenuated mitochondrial dysfunction following SCI. Further, immunohistochemical analyses of the spinal cords of treated animals showed significantly lower ROS, cleaved caspase-3, and *

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“…Briefly, mitochondrial dysfunction occur in models of inflammatory peripheral neuropathy. Sajic et al (2018) found that in experimental autoimmune neuritis (a Guillain-Barre model), mitochondria in large and small diameter axons had depolarized, fragmented, and immobile mitochondria. The depolarized mitochondria in small diameter axons appeared to create a “plug” in the axon and even obstructed the traffick of other organelles ( Sajic et al, 2018 ).…”

Section: Hdac6 and Mitochondrial Dysfunction In Peripheral Neuropathymentioning

confidence: 99%

“… Sajic et al (2018) found that in experimental autoimmune neuritis (a Guillain-Barre model), mitochondria in large and small diameter axons had depolarized, fragmented, and immobile mitochondria. The depolarized mitochondria in small diameter axons appeared to create a “plug” in the axon and even obstructed the traffick of other organelles ( Sajic et al, 2018 ). Schwann cell mitochondria have also been found to be morphologically and functionally altered as well ( Muke et al, 2020 ).…”

Section: Hdac6 and Mitochondrial Dysfunction In Peripheral Neuropathymentioning

confidence: 99%

HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

English

Barton

2021

Front. Mol. Neurosci.

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Peripheral neuropathy, which is the result of nerve damage from lesions or disease, continues to be a major health concern due to the common manifestation of neuropathic pain. Most investigations into the development of peripheral neuropathy focus on key players such as voltage-gated ion channels or glutamate receptors. However, emerging evidence points to mitochondrial dysfunction as a major player in the development of peripheral neuropathy and resulting neuropathic pain. Mitochondrial dysfunction in neuropathy includes altered mitochondrial transport, mitochondrial metabolism, as well as mitochondrial dynamics. The mechanisms that lead to mitochondrial dysfunction in peripheral neuropathy are poorly understood, however, the Class IIb histone deacetylase (HDAC6), may play an important role in the process. HDAC6 is a key regulator in multiple mechanisms of mitochondrial dynamics and may contribute to mitochondrial dysregulation in peripheral neuropathy. Accumulating evidence shows that HDAC6 inhibition is strongly associated with alleviating peripheral neuropathy and neuropathic pain, as well as mitochondrial dysfunction, in in vivo and in vitro models of peripheral neuropathy. Thus, HDAC6 inhibitors are being investigated as potential therapies for multiple peripheral neuropathic disorders. Here, we review emerging studies and integrate recent advances in understanding the unique connection between peripheral neuropathy and mitochondrial dysfunction through HDAC6-mediated interactions.

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Mitochondrial damage and “plugging” of transport selectively in myelinated, small-diameter axons are major early events in peripheral neuroinflammation

Cited by 15 publications

References 52 publications

High Dietary Fat Consumption Impairs Axonal Mitochondrial FunctionIn Vivo

High Dietary Fat Consumption Impairs Axonal Mitochondrial FunctionIn Vivo

Nanoparticles with antioxidant enzymes protect injured spinal cord from neuronal cell apoptosis by attenuating mitochondrial dysfunction

HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

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