Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

Schiavon, Cara R.; Manor, Uri

doi:10.20944/preprints202011.0227.v1

Cited by 3 publications

(3 citation statements)

References 123 publications

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“…Defects in mitochondrial dynamics disrupt the allocation of mtDNA throughout the network and subsequently lead to mitochondrial dysfunction and increased ROS. Three of the 4 other (97). Thus, our potential finding of peripheral neuropathy-related genes in CVS fits well into our ions and energy cellular model.…”

Section: Genes Not In the Above Categories And Potential Relationship...supporting

confidence: 79%

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Bar¹,

Ebenau²,

Weiner³

et al. 2023

Front. Neurol.

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ObjectiveTo utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting.MethodsA retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. “Qualifying” variants were defined as coding, rare, and conserved. Additionally, “Key Qualifying” variants were Pathogenic/Likely Pathogenic, or “Clinical” based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system.ResultsThirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as “Highly likely” (SCN4A, CACNA1A, CACNA1S, RYR2, TRAP1, MEFV) or “Likely” (SCN9A, TNFRSF1A, POLG, SCN10A, POGZ, TRPA1) CVS related. Nine additional genes (OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3, PPM1D, CHAMP1, HMBS) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant (p < 0.0001, p = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, post-analyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as “Possibly” CVS related.ConclusionAll 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the non-paroxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS.

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Section: Genes Not In the Above Categories And Potential Relationship...supporting

confidence: 79%

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Bar¹,

Ebenau²,

Weiner³

et al. 2023

Front. Neurol.

View full text Add to dashboard Cite

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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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“…Together, our findings position INF2 and ER-actin at ERorganelle contacts as important regulatory factors for both organelle morphology and transport, key features that must be dynamically modulated to maintain proper organelle and cellular function. We speculate these effects may be important for the pathophysiology of Charcot-Marie-Tooth disease mutations in INF2 27 .…”

mentioning

confidence: 91%

INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement

Schiavon,

Wang,

Feng

et al. 2024

Preprint

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Proper regulation of organelle dynamics is critical for cellular function, but the mechanisms coordinating multiple organelles remain poorly understood. Here we show that actin polymerization mediated by the endoplasmic reticulum (ER)-anchored formin INF2 acts as a master regulator of organelle morphology and movement. Using high-resolution imaging, we demonstrate that INF2-polymerized actin filaments assemble at ER contact sites on mitochondria, endosomes, and lysosomes just prior to their fission. Genetic manipulation of INF2 activity alters the size, shape and motility of all three organelles. Our findings reveal a conserved mechanism by which the ER uses actin polymerization to control diverse organelles, with implications for understanding organelle dysfunction in neurodegenerative and other diseases. This work establishes INF2-mediated actin assembly as a central coordinator of organelle dynamics and inter-organelle communication.

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Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

Cited by 3 publications

References 123 publications

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement

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