title: Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-γ inhibition.
abstract: We hypothesized that competition between nucleotide reverse-transcriptase inhibitor triphosphate and endogenous deoxyribonucleotide triphosphate (dNTP) may lead to depletion of dNTP pools and mitochondrial dysfunction independent of polymerase-γ (pol-γ) inhibition. We collected peripheral blood mononuclear cells from 75 adults (25 cases: HIV-infected patients with mitochondrial toxicity, 25 HIV-infected positive controls, and 25 HIV-negative controls). We observed statistically significant individual and group differences in ribonucleotide (RN) and deoxyribonucleotide (dRN) pools. The median values for the RN pools were 10,062 (interquartile range (IQR): 7,090-12,590), 4,360 (IQR: 3,058-6,838), and 2,968 (IQR: 2,538-4,436) pmol/10(6) cells for negative controls, positive controls, and cases, respectively. Cases had significantly higher absolute mitochondrial DNA copy number as compared with negative controls (P < 0.05). Moreover, cases had significantly higher expression levels of pol-γ, nucleotide transporters, cellular kinases, and adenosine triphosphate (ATP)-binding cassette (ABC) proteins as compared with controls. Antiretroviral therapy (ART) perturbs RN and dRN pools. Depletion of RN and dRN pools may be associated with ART-induced mitochondrial toxicity independent of pol-γ inhibition.
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: S
authors.initials: S
authors.lastname: Selvaraj
authors.affiliation: Harvard Medical School and Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ghebremichael
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Foli
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: A
authors.initials: A
authors.lastname: Langs-Barlow
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ogbuagu
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: L
authors.initials: L
authors.lastname: Barakat
authors.affiliation: Georgetown University, Washington, DC, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tubridy
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: R
authors.initials: R
authors.lastname: Edifor
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: W
authors.initials: W
authors.lastname: Lam
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: 1] Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA [2] Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: E
authors.initials: E
authors.lastname: Paintsil
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D019380:Anti-HIV Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000097:blood; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000097:blood; D005260:Female; D018628:Gene Dosage; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors; D033704:Nucleotide Transport Proteins / Q000378:metabolism; D009711:Nucleotides / Q000009:adverse effects*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D012265:Ribonucleotides / Q000097:blood
chemical_list: D018528:ATP-Binding Cassette Transporters; D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D003854:Deoxyribonucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D033704:Nucleotide Transport Proteins; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D012265:Ribonucleotides; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase