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Activity-dependent regulation of mitochondrial motility by calcium and Na/K-ATPase at nodes of Ranvier of myelinated nerves.

ABSTRACT: The node of Ranvier is a tiny segment of a myelinated fiber with various types of specializations adapted for generation of high-speed nerve impulses. It is ionically specialized with respect to ion channel segregation and ionic fluxes, and metabolically specialized in ionic pump expression and mitochondrial density augmentation. This report examines the interplay of three important parameters (calcium fluxes, Na pumps, mitochondrial motility) at nodes of Ranvier in frog during normal nerve activity. First, we used calcium dyes to resolve a highly localized elevation in axonal calcium at a node of Ranvier during action potentials, and showed that this calcium elevation retards mitochondrial motility during nerve impulses. Second, we found, surprisingly, that physiologic activation of the Na pumps retards mitochondrial motility. Blocking Na pumps alone greatly prevents action potentials from retarding mitochondrial motility, which reveals that mitochondrial motility is coupled to Na/K-ATPase. In conclusion, we suggest that during normal nerve activity, Ca elevation and activation of Na/K-ATPase act, possibly in a synergistic manner, to recruit mitochondria to a node of Ranvier to match metabolic needs.

SUBMITTER: Zhang CL

PROVIDER: S-EPMC3548432 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Activity-dependent regulation of mitochondrial motility by calcium and Na/K-ATPase at nodes of Ranvier of myelinated nerves.

Zhang Chuan Li CL Ho Po Lai PL Kintner Douglas B DB Sun Dandan D Chiu Shing Yan SY

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100301 10

The node of Ranvier is a tiny segment of a myelinated fiber with various types of specializations adapted for generation of high-speed nerve impulses. It is ionically specialized with respect to ion channel segregation and ionic fluxes, and metabolically specialized in ionic pump expression and mitochondrial density augmentation. This report examines the interplay of three important parameters (calcium fluxes, Na pumps, mitochondrial motility) at nodes of Ranvier in frog during normal nerve acti ...[more]

PMID: 20219989

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Project description:The mechanisms that govern node of Ranvier organization, stability, and long-term maintenance remain to be fully elucidated. One of the molecular components of the node is the cytoskeletal scaffolding protein, ankyrin G (AnkG), which interacts with multiple members of the nodal complex. The role of AnkG in nodal organization and maintenance is still not clearly defined as to whether AnkG functions as an initial nodal organizer or whether it functions as a nodal stabilizer after the nodal complex has been assembled. Using a mouse model system, we report here that perinatal and juvenile neuronal ablation of AnkG has differential consequences on nodal stability. Early loss of AnkG creates immature nodes with abnormal morphology, which undergo accelerated destabilization within a month, resulting in rapid voltage-gated sodium (NaV) channel and βIV spectrin loss with reduced effects on neurofascin 186. On the other hand, late ablation of AnkG from established nodal complexes leads to slow but progressive nodal destabilization over 10 months, primarily affecting βIV spectrin, followed by NaV channels, with modest impact on neurofascin 186. We also show that ankyrin R and βI spectrin are not sufficient to prevent nodal disorganization after AnkG ablation. Additionally, nodal disorganization in both early and late AnkG mutants is accompanied by axonal pathology and neurological dysfunction. Together, our results suggest that AnkG plays an indispensable role in the maturation and long-term stabilization of the newly assembled nodal complex, and that loss of AnkG after nodal stabilization does not lead to rapid nodal disassembly but to loss of specific nodal components in a time-dependent manner.SIGNIFICANCE STATEMENT Nodes of Ranvier are the myelin-free gaps along myelinated axons that allow fast communication between neurons and their target cells by propagating action potentials in a saltatory manner. The cytoskeletal scaffolding protein ankyrin G (AnkG) has been thought to play an important role in node formation; however, its precise role in nodal assembly, stability, and maintenance is still not clear. By using spatiotemporal ablation of AnkG, we report its differential role in nodal maturation and stabilization. We show that early AnkG-deficient nodes fail to mature and undergo rapid destabilization. In contrast, nodes that assemble with AnkG are much more stable and undergo gradual disintegration with sequential loss of nodal components in the absence of AnkG.

Project description:Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP) and chronic idiopathic axonal polyneuropathies (CIAP). The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70 ± 4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP and the alterations in paranodin immunofluorescence may be an interesting tool for their differential diagnosis.

Dataset Information

Activity-dependent regulation of mitochondrial motility by calcium and Na/K-ATPase at nodes of Ranvier of myelinated nerves.

Publications

Activity-dependent regulation of mitochondrial motility by calcium and Na/K-ATPase at nodes of Ranvier of myelinated nerves.

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