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Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy

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Abstract

Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy.

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Acknowledgments

This work is supported by the Chemistry Core of the MDRTC for mouse plasma insulin and GHb measurements. This work was supported by the Juvenile Diabetes Research Foundation (AMV, ELF), the American Diabetes Association (AMV), the Animal Models of Diabetes Complications Consortium (AMDCC; NIH UO1 DK076160, ELF), the Program for Neurology Research and Discovery (JLE), the A. Alfred Taubman Medical Institute (AMV, JLE, ELF), the Instituto Superiore di Sanita (AQ), and FIRB (AQ).

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Authors and Affiliations

  1. Department of Neurology, University of Michigan, 5371 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA

    Andrea M. Vincent, Lisa L. McLean, Yu Hong & Eva L. Feldman

  2. Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, MD, 20850, USA

    James L. Edwards

  3. Department of Neurology, INSPE San Raffaele Scientific Institute, Milan, Italy

    Federica Cerri, Ignazio Lopez & Angelo Quattrini

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  1. Andrea M. Vincent
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  2. James L. Edwards
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  3. Lisa L. McLean
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  4. Yu Hong
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  5. Federica Cerri
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  6. Ignazio Lopez
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  8. Eva L. Feldman
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Correspondence to Andrea M. Vincent.

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Vincent, A.M., Edwards, J.L., McLean, L.L. et al. Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy. Acta Neuropathol 120, 477–489 (2010). https://doi.org/10.1007/s00401-010-0697-7

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  • DOI: https://doi.org/10.1007/s00401-010-0697-7

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