Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

Schiavon, Cara R.; Shadel, Gerald S.; Manor, Uri

doi:10.3389/fcell.2021.624823

Cited by 29 publications

(27 citation statements)

References 251 publications

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“…Among the 80+ genes implicated in CMT, many are known to regulate axonal transport of cellular components, including mitochondria, suggesting that impaired axonal transport can contribute to the pathology of peripheral neuropathy ( Schiavon et al, 2021 ). In this sense, reduced mitochondrial transport in long peripheral neurons is proposed to lead to insufficient energy at the ends of axons.…”

Section: Overview Of Mfn2 Functions Impacted By Mfn2 Variantsmentioning

confidence: 99%

“…Impairments in mitochondrial dynamics are often linked to peripheral neuropathies ( Sharma et al, 2021a ). One way through which impaired mitochondrial dynamics are thought to contribute to peripheral neuropathy is via reduced mitochondrial motility ( Schiavon et al, 2021 ), which can occur bi-directionally along axons ( O’Toole et al, 2008 ; Saxton and Hollenbeck, 2012 ). Mitochondrial transport is obviously important in the long axons found in neurons, as synapses present in the distal region of neurons require mitochondria to provide the energy.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

Zaman

Shutt

2022

Front. Cell Dev. Biol.

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The Mitofusin 2 protein (MFN2), encoded by the MFN2 gene, was first described for its role in mediating mitochondrial fusion. However, MFN2 is now recognized to play additional roles in mitochondrial autophagy (mitophagy), mitochondrial motility, lipid transfer, and as a tether to other organelles including the endoplasmic reticulum (ER) and lipid droplets. The tethering role of MFN2 is an important mediator of mitochondrial-ER contact sites (MERCs), which themselves have many important functions that regulate mitochondria, including calcium homeostasis and lipid metabolism. Exemplifying the importance of MFN2, pathogenic variants in MFN2 are established to cause the peripheral neuropathy Charcot-Marie-Tooth Disease Subtype 2A (CMT2A). However, the mechanistic basis for disease is not clear. Moreover, additional pathogenic phenotypes such as lipomatosis, distal myopathy, optic atrophy, and hearing loss, can also sometimes be present in patients with CMT2A. Given these variable patient phenotypes, and the many cellular roles played by MFN2, the mechanistic underpinnings of the cellular impairments by which MFN2 dysfunction leads to disease are likely to be complex. Here, we will review what is known about the various functions of MFN2 that are impaired by pathogenic variants causing CMT2A, with a specific emphasis on the ties between MFN2 variants and MERCs.

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Section: Overview Of Mfn2 Functions Impacted By Mfn2 Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

Zaman

Shutt

2022

Front. Cell Dev. Biol.

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“…In CIPN, inhibition of HDAC6 improved axonal transport of mitochondria, which correlated with repaired nerve fibers and α-tubulin acetylation ( Ma et al, 2019 ). For CMT disordes, particularly CMT2, it has been well established that axonal mitochondrial transport is impaired in patients and mouse models of CMT2 though other factors such as genetics play an important role ( Schiavon et al, 2021 ). Mutated Mitofusin 2, a gene mutated in CMT2, led to clustering of mitochondria due to diminished movement along axons ( Baloh et al, 2007 ).…”

Section: Mitochondrial Transport Is Altered In Models Of 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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“…While impaired mitochondrial transport is typically thought to explain the peripheral neuropathy phenotype associated with pathogenic variants in genes regulating mitochondrial dynamics, there is likely more to the story. For example, while the length of peripheral axons is proposed to explain their sensitivity to reduced mitochondrial motility, the CNS axons of humans, which do not necessarily show degeneration when motility is impaired, can be longer than peripheral neurons in mice, which do exhibit peripheral neuropathy [338]. Thus, impaired transport down long neurons alone is insufficient to explain why peripheral neurons are sensitive to impaired mitochondrial dynamics.…”

Section: Mitochondrial Dynamics and Quality Control In Peripheral Neuropathymentioning

confidence: 99%

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

Sharma

Pfeffer

Shutt

2021

Biology

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Mitochondria are dynamic organelles capable of fusing, dividing, and moving about the cell. These properties are especially important in neurons, which in addition to high energy demand, have unique morphological properties with long axons. Notably, mitochondrial dysfunction causes a variety of neurological disorders including peripheral neuropathy, which is linked to impaired mitochondrial dynamics. Nonetheless, exactly why peripheral neurons are especially sensitive to impaired mitochondrial dynamics remains somewhat enigmatic. Although the prevailing view is that longer peripheral nerves are more sensitive to the loss of mitochondrial motility, this explanation is insufficient. Here, we review pathogenic variants in proteins mediating mitochondrial fusion, fission and transport that cause peripheral neuropathy. In addition to highlighting other dynamic processes that are impacted in peripheral neuropathies, we focus on impaired mitochondrial quality control as a potential unifying theme for why mitochondrial dysfunction and impairments in mitochondrial dynamics in particular cause peripheral neuropathy.

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Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

Cited by 29 publications

References 251 publications

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

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

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

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