Axonal mitochondria adjust in size depending on <i>g</i>‐ratio of surrounding myelin during homeostasis and advanced remyelination

Ineichen, Benjamin Victor; Zhu, Kun; Carlström, Karl E.

doi:10.1002/jnr.24767

Cited by 16 publications

(19 citation statements)

References 47 publications

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“…Axonal mitochondria have a tubular-like appearance with diameters between 50 nm and 300 nm [ 22 , 50 ] and lengths less than 2 µm [ 51 ]. The size in our model was set to 1 µm, close to the reported median [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy

Lambiri

Levin

2022

Biomolecules

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Leber hereditary optic neuropathy (LHON) is a rare syndrome that results in vision loss. A necessary but not sufficient condition for its onset is the existence of known mitochondrial DNA mutations that affect complex I biomolecular structure. Cybrids with LHON mutations generate higher rates of reactive oxygen species (ROS). This study models how ROS, particularly H2O2, could signal and execute the axonal degeneration process that underlies LHON. We modeled and explored several hypotheses regarding the influence of H2O2 on the dynamics of propagation of axonal degeneration in LHON. Zonal oxidative stress, corresponding to H2O2 gradients, correlated with the morphology of injury exhibited in the LHON pathology. If the axonal membrane is highly permeable to H2O2 and oxidative stress induces larger production of H2O2, small injuries could trigger cascading failures of neighboring axons. The cellular interdependence created by H2O2 diffusion, and the gradients created by tissue variations in H2O2 production and scavenging, result in injury patterns and surviving axonal loss distributions similar to LHON tissue samples. Specifically, axonal degeneration starts in the temporal optic nerve, where larger groups of small diameter fibers are located and propagates from that region. These findings correlate well with clinical observations of central loss of visual field, visual acuity, and color vision in LHON, and may serve as an in silico platform for modeling the mechanism of action for new therapeutics.

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Section: Methodsmentioning

confidence: 99%

Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy

Lambiri

Levin

2022

Biomolecules

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“…Under conditions of high energy demand or mitochondrial dysfunction, increased amounts of ROS are produced. In CNS disorders, mitochondrial dysfunction has mainly been described in neurons [77,78] and even in relation to myelin thickness [73], but less is known about oligodendrocytes or OPCs. Studies on non-mitochondrial intracellular ROS/RNS sources in OPCs and oligodendrocytes are also limited, but include inducible nitric oxide synthase (iNOS), neuronal NOS (nNOS) [79][80][81] and NADPH oxidase (NOX) enzymes [82,83], as well as peroxisomal lipid metabolism [84].…”

Section: Physiology and Sources Of Oxidative/nitrosative And Carbonylmentioning

confidence: 99%

“…Once oligodendrocytes have ensheathed neuronal axons they can shuttle lactate/pyruvate via the MCT1 monocarboxylate transporter [ 59 , 71 , 72 ]. In addition, it was recently demonstrated that axons with thinner myelin sheaths had larger axonal mitochondria, further underscoring the importance of oligodendrocytes for neuronal health [ 73 ].…”

Section: From Opc To Oligodendrocytementioning

confidence: 99%

Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders

Spaas

Veggel

Schepers

et al. 2021

Cell. Mol. Life Sci.

118

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Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.

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“…Furthermore, the results of TEM showed that the myelin sheaths of the control mice had the perfect SC basal membrane and the lamella densely surrounded the regenerated axons, while in the Etv1-siRNA treated groups, SC myelination was abnormal, manifesting as hypermyelination or hypomyelination. Quantitative analysis showed that the ratio of myelinated/unmyelinated axons, the myelin sheath layer number, and the myelin sheath thickness were all lower, while g-ratio, a reliable axonal myelination index ( 34 ), was higher in the Etv1 knockdown mice than in the control ( Figure 3B .b3). Together, these observations suggested that Etv1 regulates SC re-myelination in vivo .…”

Section: Resultsunclassified

The Etv1/Er81 transcription factor coordinates myelination-related genes to regulate Schwann cell differentiation and myelination

Askar¹,

Xu²,

Hu³

et al. 2022

Ann Transl Med

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Background: Axonal myelination is critical for the functioning of vertebrate nervous system. Myelin sheath malformation or degeneration can cause a variety of neurological diseases. Our previous study identified multiple potential myelination-related transcriptional factors (TFs), including expressed sequence tag (ETS) variant transcription factor 1 (Etv1)/Er81, via gene microarray analysis of Schwann cells (SCs) at various myelination stages. Etv1 is known to be involved in the regulation of neuronal specialization, muscle spindle differentiation, and sensorimotor connectivity. However, to our knowledge, to date, there are no relevant studies that Etv1 regulates SC myelination. Methods: To investigate the roles of Etv1 in SC re-myelination, an in vivo mouse myelination model was used, in which the sciatic nerve is crushed. Etv1 in nerves was knocked down via in situ injection of cholesterol-modified Etv1-small interfering (si)RNA. The expression of myelin-associated glycoprotein (MAG) was evaluated by Western blotting (WB) and immunohistochemistry (IHC). Myelination was assessed by transmission electron microscopy (TEM). The effects of Etv1 on SC proliferation, migration, and differentiation were assessed in vitro using the EdU cell proliferation kit, a culture-insert scratch assay, a SC aggregate sphere migration assay on the axons of dorsal root ganglions (DRGs), and a SC differentiation model. Chromatin immunoprecipitation (ChIP) united with quantitative real-time PCR (qPCR), known as ChIP-qPCR, and luciferase activity reporter assays were performed to explore the possible mechanisms by which Etv1 controls SC differentiation and myelination. Results: The results demonstrated that Etv1 promoted myelination by facilitating SC proliferation, migration, and differentiation. Etv1 expression in SCs was upregulated during re-myelination, and knocking down Etv1 expression dramatically abrogated SC re-myelination in the crushed sciatic nerves. Moreover, silencing of Etv1 by siRNA in SCs in vitro inhibited its migration, proliferation, and differentiation. The results of ChIP-qPCR and luciferase reporter assay showed that Etv1 may regulate SC differentiation and myelination by binding to the promoters of myelination-related genes, such as MAG and Runx2, to initiate their transcription. Conclusions: Taken together, these findings demonstrated a previously unknown role of Etv1 in SC differentiation and myelination, providing a candidate molecular target for clinical interventions in demyelinating diseases.

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Axonal mitochondria adjust in size depending on g‐ratio of surrounding myelin during homeostasis and advanced remyelination

Cited by 16 publications

References 47 publications

Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy

Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy

Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders

The Etv1/Er81 transcription factor coordinates myelination-related genes to regulate Schwann cell differentiation and myelination

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