Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2'3'-dideoxycytidine (ddC)

Lab Invest. 2001 Nov;81(11):1537-44. doi: 10.1038/labinvest.3780367.


The 2'3'-dideoxycytidine (ddC), a nonazylated dideoxynucleoside analog used for the treatment of AIDS, causes a dose-dependent, painful, sensorimotor axonal peripheral neuropathy in up to 30% of the patients. To investigate the cause of the neuropathy, we performed morphological and molecular studies on nerve biopsy specimens from well-selected patients with ddC-neuropathy and from control subjects with disease, including patients with AIDS-related neuropathy never treated with ddC. Because ddC, in vitro, inhibits the replication of mitochondrial DNA (mtDNA), we counted the number of normal and abnormal mitochondria in a 0.04 mm(2) cross-sectional area of the nerves and quantified the copy numbers of mtDNA by competitive PCR in all specimens. A varying degree of axonal degeneration was present in all nerves. Abnormal mitochondria with enlarged size, excessive vacuolization, electron-dense concentric inclusions and degenerative myelin structures were prominent in the ddC-neuropathy and accounted for 55% +/- 2.5% of all counted mitochondria in the axon and Schwann cells, compared with 9% +/- 0.7% of the controls (p < 0.001). Significantly (p < 0.005) reduced copy numbers, with as high as 80% depletion, of the mtDNA was demonstrated in the nerves of the ddC-treated patients compared with the controls. We conclude that ddC induces a mitochondrial neuropathy with depletion of the nerve's mtDNA. The findings are consistent with the ability of ddC to selectively inhibit the gamma-DNA polymerase in neuronal cell lines. Toxicity to mitochondria of the peripheral nerve is a new cause of acquired neuropathy induced by exogenous toxins and may be the cause of neuropathy associated with the other neurotoxic antiretroviral drugs or toxic-metabolic conditions.

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy*
  • Adult
  • Anti-HIV Agents / adverse effects*
  • DNA, Mitochondrial / metabolism*
  • Humans
  • Microscopy, Electron
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / ultrastructure
  • Peripheral Nervous System Diseases / chemically induced*
  • Peripheral Nervous System Diseases / pathology
  • Peripheral Nervous System Diseases / virology
  • Schwann Cells / pathology
  • Sural Nerve / pathology
  • Zalcitabine / adverse effects*


  • Anti-HIV Agents
  • DNA, Mitochondrial
  • Zalcitabine