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.
journal_name
Ann Neuroljournal_title
Annals of neurologyauthors
Lehmann HC,Chen W,Borzan J,Mankowski JL,Höke Adoi
10.1002/ana.22150subject
Has Abstractpub_date
2011-01-01 00:00:00pages
100-10issue
1eissn
0364-5134issn
1531-8249journal_volume
69pub_type
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journal_title:Annals of neurology
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journal_title:Annals of neurology
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journal_title:Annals of neurology
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pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1002/ana.21079
更新日期:2007-01-01 00:00:00
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pub_type: 临床试验,杂志文章
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pub_type: 杂志文章
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更新日期:1992-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/ana.10724
更新日期:2003-10-01 00:00:00
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更新日期:2007-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/ana.25726
更新日期:2020-07-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410160614
更新日期:1984-12-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410020413
更新日期:1977-10-01 00:00:00
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pub_type: 杂志文章
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更新日期:2008-03-01 00:00:00
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更新日期:2015-03-01 00:00:00
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pub_type: 杂志文章,评审
doi:10.1002/ana.21289
更新日期:2007-10-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章,评审
doi:
更新日期:2000-04-01 00:00:00
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pub_type: 杂志文章,评审
doi:10.1002/ana.20743
更新日期:2005-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:2016-06-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
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更新日期:1994-06-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.20474
更新日期:2005-05-01 00:00:00