Schwann cell mitochondrial metabolism supports long-term axonal survival and peripheral nerve function

Mitochondrial dysfunction is a common cause of peripheral neuropathies. While the role of neuron and axonal mitochondria in peripheral nerve disease is well appreciated, whether Schwann cell (SC) mitochondrial deficits contribute to peripheral neuropathies is unclear. Here, we examine how SC mitocho...

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Bibliographic Details
Published in:The Journal of neuroscience 2011-07, Vol.31 (28), p.10128-10140
Main Authors: Viader, Andreu, Golden, Judith P, Baloh, Robert H, Schmidt, Robert E, Hunter, Daniel A, Milbrandt, Jeffrey
Format: Article
Language:English
Subjects:
Animals
Axons - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
High Mobility Group Proteins - genetics
High Mobility Group Proteins - metabolism
Mice
Mitochondria - genetics
Mitochondria - metabolism
Myelin Sheath - metabolism
Neurons - metabolism
Peripheral Nerves - metabolism
Schwann Cells - metabolism
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Summary:Mitochondrial dysfunction is a common cause of peripheral neuropathies. While the role of neuron and axonal mitochondria in peripheral nerve disease is well appreciated, whether Schwann cell (SC) mitochondrial deficits contribute to peripheral neuropathies is unclear. Here, we examine how SC mitochondrial dysfunction affects axonal survival and contributes to the decline of peripheral nerve function by generating mice with SC-specific mitochondrial deficits. These mice (Tfam-SCKOs) were produced through the tissue-specific deletion of the mitochondrial transcription factor A gene (Tfam), which is essential for mitochondrial DNA (mtDNA) transcription and maintenance. Tfam-SCKOs were viable, but as they aged, they developed a progressive peripheral neuropathy characterized by nerve conduction abnormalities as well as extensive muscle denervation. Morphological examination of Tfam-SCKO nerves revealed early preferential loss of small unmyelinated fibers followed by prominent demyelination and degeneration of larger-caliber axons. Tfam-SCKOs displayed sensory and motor deficits consistent with this pathology. Remarkably, the severe mtDNA depletion and respiratory chain abnormalities in Tfam-SCKO mice did not affect SC proliferation or survival. Mitochondrial function in SCs is therefore essential for maintenance of axonal survival and normal peripheral nerve function, suggesting that SC mitochondrial dysfunction contributes to human peripheral neuropathies.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.0884-11.2011