Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy

Authors

  • Helmar C. Lehmann,

    1. Department of Neurology, Johns Hopkins University, Baltimore, MD
    2. Department of Neurology, Heinrich Heine University, Düsseldorf, Germany
    Search for more papers by this author
  • Weiran Chen,

    1. Department of Neurology, Johns Hopkins University, Baltimore, MD
    Search for more papers by this author
  • Jasenka Borzan,

    1. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD
    Search for more papers by this author
  • Joseph L. Mankowski,

    1. Department of Neurology, Johns Hopkins University, Baltimore, MD
    2. Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD
    3. Department of Pathology, Johns Hopkins University, Baltimore, MD
    Search for more papers by this author
  • Ahmet Höke

    Corresponding author
    1. Department of Neurology, Johns Hopkins University, Baltimore, MD
    2. Department of Neuroscience, Johns Hopkins University, Baltimore, MD
    • Department of Neurology, Johns Hopkins School of Medicine, John G. Rangos Sr. Building, 855 N. Wolfe St, Room 248 Neurology, Baltimore, MD 21287
    Search for more papers by this author

Abstract

Objective

Accumulation of mitochondrial DNA (mtDNA) damage has been associated with aging and abnormal oxidative metabolism. We hypothesized that in human immunodeficiency virus-associated sensory neuropathy (HIV-SN), damaged mtDNA accumulates in distal nerve segments, and that a spatial pattern of mitochondrial dysfunction contributes to the distal degeneration of sensory nerve fibers.

Methods

We measured levels of common deletion mutations in mtDNA and expression levels of mitochondrial respiratory chain complexes of matched proximal and distal nerve specimens from patients with and without HIV-SN. In mitochondria isolated from peripheral nerves of simian immunodeficiency virus (SIV)-infected macaques, a model of HIV-SN, we measured mitochondrial function and generation of reactive oxygen species.

Results

We identified increased levels of mtDNA common deletion mutation in postmortem sural nerves of patients with HIV-SN as compared to uninfected patients or HIV patients without sensory neuropathy. Furthermore, we found that common deletion mutation in mtDNA was more prevalent in distal sural nerves compared to dorsal root ganglia. In a primate model of HIV-SN, freshly isolated mitochondria from sural nerves of macaques infected with a neurovirulent strain of SIV showed impaired mitochondrial function compared to mitochondria from proximal nerve segments.

Interpretation

Our findings suggest that mtDNA damage accumulates in distal mitochondria of long axons, especially in patients with HIV-SN, and that this may lead to reduced mitochondrial function in distal nerves relative to proximal segments. Although our findings are based on HIV-SN, if confirmed in other neuropathies, these observations could explain the length-dependent nature of most axonal peripheral neuropathies. ANN NEUROL 2010

Ancillary