Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 226, Issue 1, Pages 94-106Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2007.08.015
Keywords
complex I; cAMP; protein kinase A; NRTI; superoxide
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL072715] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL072715, R01 HL072715-04, R01 HL072715-05, HL072715, R01 HL072715-03, R01 HL072715-02, R01 HL072715-01] Funding Source: Medline
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Nucleoside analog reverse transcriptase inhibitors (NRTIs) are known to directly inhibit mitochondrial complex I activity as well as various mitochondrial kinases. Recent observations that complex I activity and superoxide production are modulated through cAMP-dependent phosphorylation suggests a mechanism through which NRTIs may affect mitochondrial respiration via kinase-dependent protein phosphorylation. In the current study, we examine the potential for NRTIs to inhibit the cAMP-dependent phosphorylation of complex I and the associated NADH:CoQ oxidoreductase activities and rates of superoxide production using HepG2 cells. Phosphoprotein staining of immunocaptured complex I revealed that 3'-azido-3'-deoxythymidine (AZT; 10 and 50 mu M), AZT monophosphate (150 mu M), and 2,3'-dideoxycytidine (ddC; 1 mu M) prevented the phosphorylation of the NDUFB11 subunit of complex I. This was associated with a decrease in complex I activity with AZT and AZT monophosphate only. In the presence of succinate, superoxide production was increased with 2',3'-dideoxyinosine (ddI; 10 mu M) and ddC (1 mu M). In the presence of succinate+cAMP, AZT showed an inverse dose-dependent effect on superoxide production. None of the NRTIs examined inhibit PKA activity suggesting that the observed effects are due to a direct interaction with complex I. These data demonstrate a direct effect of NRTIs on cAMP-dependent regulation of mitochondrial bioenergetics independent of DNA polymerase-gamma activity; in the case of AZT, these observations may provide a mechanism for the observed long-term toxicity with this drug. (c) 2007 Elsevier Inc. All rights reserved.
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