Mitochondrial Alterations with Mitochondrial DNA Depletion in the Nerves of AIDS Patients with Peripheral Neuropathy Induced by 2′3′-Dideoxycytidine (ddC)

Abstract

SUMMARY: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% Ϯ 2.5% of all counted mitochondria in the axon and Schwann cells, compared with 9% Ϯ 0.7% of the controls (p Ͻ 0.001). Significantly (p Ͻ 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 ␥-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. (Lab Invest 2001, 81:1537-1544.

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

“…17 Abnormal mitochondria and mitochondrial DNA depletion have also been seen with ddI-associated PN. 18 Similarities between the clinical manifestations of inherited mitochondrial diseases and NRTI toxicities prompted us to look for variations in the mitochondrial genome that may help explain susceptibility to PN among HIV-infected persons.…”

Neuropathy‐induced apoptosis: Protective effect of physostigmine

“…It is licensed in many countries as an agent for reversing the effect of drugs and poisons causing the anticholinergic syndrome. In the present work, we show the effect of this natural compound in a model of peripheral neuropathy, a syndrome characterized by nerve damage and nervous tissue degeneration, and the role of apoptosis in tissue alterations and cell loss is widely substantiated (Dalakas et al, 2001;Andre et al, 2002;Moulder et al, 2002;Siler-Marsiglio et al, 2004;Leinninger et al, 2006;Melli et al, 2006;Di Cesare Mannelli et al, 2007).…”

“…Mitochondrial membrane permeabilization causes release of cytochrome C and the subsequent formation of a complex that initiates cleavage and activation of caspases (Dalakas et al, 2001;Andre et al, 2002;Moulder et al, 2002;Siler-Marsiglio et al, 2004;Leinninger et al, 2006;Melli et al, 2006).…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…18 Indeed, increased numbers of abnormal mitochondria in nerves and significantly reduced cellular mtDNA content were evidenced in patients treated with ddC (zalcitabine). 19 Beyond inhibition of the mitochondrial DNA polymerase-␥, NRTIs have direct effect on mitochondrial membrane potential inducing energy failure and subsequent axonal degeneration in DRG cultures without neuronal loss. 20,21 Their toxicity could be even aggravated by pre-existing HIV-mediated mitochondrial defects.…”