Disrupted axo-glial junctions result in accumulation of abnormal mitochondria at nodes of Ranvier

Abstract

Mitochondria and other membranous organelles are frequently enriched in the nodes and paranodes of peripheral myelinated axons, particularly those of large caliber. The physiologic role(s) of this organelle enrichment and the rheologic factors that regulate it are not well understood. Previous studies suggest that axonal transport of organelles across the nodal/paranodal region is locally regulated. In this study, we have examined the ultrastructure of myelinated axons in the sciatic nerves of mice deficient in the contactin-associated protein (Caspr), an integral junctional component. These mice, which lack the normal septate-like junctions that promote attachment of the glial (paranodal) loops to the axon, contain aberrant mitochondria in their nodal/ paranodal regions. These mitochondria are typically large and swollen and occupy prominent varicosities of the nodal axolemma. In contrast, mitochondria located outside the nodal/paranodal regions of the myelinated axons appear normal. These findings suggest that paranodal junctions regulate mitochondrial transport and function in the axoplasm of the nodal/paranodal region of myelinated axons of peripheral nerves. They further implicate the paranodal junctions in playing a role, either directly or indirectly, in the local regulation of energy metabolism in the nodal region.

In vivo time-lapse imaging of mitochondria in healthy and diseased peripheral myelin sheath

“…Moreover we have shown that mitochondria are more abundant in the perinuclear cytoplasm and in paranodal loops where they localize both in the inner adaxonal part and in the outer abaxonal part. This enrichment in paranodal loops in interesting because axonal mitochondria have been shown to be abundant in paranodes (Zhang et al, 2010), where an unclear mechanism appears to sequester them (Einheber et al, 2006). So this suggests that glial and axonal mitochondria may functionally or metabolically interact in these paranodal regions, where they are more closely localized.…”

Distribution of mitochondria along small‐diameter myelinated central nervous system axons

“…Our results do not exclude the possibility that, in highly active states, with a high frequency of action potentials, the situation may change. In the PNS, the molecular composition of the paranodal region can influence the local accumulation of mitochondria (Einheber et al, 2007), and it is possible that their localization in the CNS is temporally adjusted to meet changes in energy requirements.…”

“…It is often stated in the literature that they are also enriched in the nodal regions of myelinated axons, where metabolic demand is high (Chada and Hollenbeck, 2004;Reynolds et al, 2004;Hollenbeck and Saxton, 2005). Although this may be true in the peripheral nervous system Einheber et al, 2007), it is not, in our experience of examining rodent, canine, and feline white matter, the case in normal small-diameter CNS axons. As part of our research into mechanisms of axonal degeneration in HSP and MS, we undertook to determine 1) whether the paranode-node-paranode (PNP) regions of small-diameter CNS axons (where metabolic demand might be ex-pected to be high) contained disproportionately more mitochondria than internodal regions and 2) whether there was any difference in mitochondrial numbers between proximal and distal regions of such axons.…”

Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves

“…Deficiency in either caspr, contactin, or neurofascin 155 produces a disorganization of the paranodal loops and a reduction in axon conduction velocity (Bhat et al, 2001;Bonnon et al, 2007;Boyle et al, 2001;Sherman et al, 2005). At the nodal/paranodal region in the myelinated axons of sciatic nerves of mice deficient in caspr, PJBs were missing and abnormal, swollen mitochondria were observed (Einheber et al, 2006). In contrast, mitochondria located in the axoplasm outside this region appeared normal, suggesting that the PJB influences mitochondrial function and perhaps transport in the axoplasm of the nodal/paranodal region of myelinated axons of peripheral nerves.…”