Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy
- 8 November 2010
- journal article
- research article
- Published by Wiley in Annals of Neurology
- Vol. 69 (1), 100-110
- https://doi.org/10.1002/ana.22150
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 2010Keywords
This publication has 51 references indexed in Scilit:
- A Simian Immunodeficiency Virus-Infected Macaque Model To Study Viral Reservoirs That Persist during Highly Active Antiretroviral TherapyJournal of Virology, 2009
- Altered cutaneous nerve regeneration in a simian immunodeficiency virus / macaque intracutaneous axotomy modelJournal of Comparative Neurology, 2009
- Natural Host Genetic Resistance to Lentiviral CNS Disease: A Neuroprotective MHC Class I Allele in SIV-Infected MacaquesPLOS ONE, 2008
- Functional Trade-Offs in White Matter Axonal ScalingJournal of Neuroscience, 2008
- Peripheral Insensate Neuropathy—A Tall Problem for US Adults?American Journal of Epidemiology, 2006
- Ions, energy and axonal injury: towards a molecular neurology of multiple sclerosisTrends in Molecular Medicine, 2006
- A novel endogenous erythropoietin mediated pathway prevents axonal degenerationAnnals of Neurology, 2004
- Region-specific analysis of mitochondrial DNA deletions in neurodegenerative disorders in humansNeuroscience Letters, 2004
- Ageing-associated 5 kb deletion in human liver mitochondrial DNABiochemical and Biophysical Research Communications, 1991
- Age-dependent increase in deleted mitochondrial DNA in the human heart: Possible contributory factor to presbycardiaAmerican Heart Journal, 1991