In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA.
BACKGROUND
Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described.


METHODS
We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks.


RESULTS
We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues.


CONCLUSIONS
Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.
Mallon
Patrick W G
PW
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, NSW 2010, Australia. p.mallon@cfi.unsw.edu.au
Unemori
Patrick
P
Sedwell
Rebecca
R
Morey
Adrienne
A
Rafferty
Martina
M
Williams
Kenneth
K
Chisholm
Donald
D
Samaras
Katherine
K
Emery
Sean
S
Kelleher
Anthony
A
Cooper
David A
DA
Carr
Andrew
A
D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D000368:Aged; D001823:Body Composition / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015854:Up-Regulation
D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors