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

TitleMitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy
Publication TypeJournal Article
Year of Publication2011
AuthorsLehmann, HC, Chen, W, Borzan, J, Mankowski, JL, Höke, A
JournalAnnals of Neurology
Date Published2011
KeywordsAcquired Immunodeficiency Syndrome, Adult, Aged, Animal, Animals, Axons, Disease Models, DNA, DNA Damage, External, Female, HIV Infections, Humans, Macaca fascicularis, Macaca nemestrina, Male, Middle Aged, Mitochondria, Mitochondrial, Per

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.