The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolidrelated hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P ‫؍‬ 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.Linezolid belongs to a family of antibiotics (oxazolidinones) that inhibit bacterial protein synthesis by binding to 23S rRNA in the large ribosomal subunit and preventing the fusion of 30S and 50S ribosomal subunits and the formation of the translation initiation complex (1). It has shown excellent efficacy against gram-positive cocci, including Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and streptococci, with MICs ranging from 0.5 to 4 mg/liter (16). Furthermore, linezolid has 100% oral bioavailability and reaches high concentrations at different sites (skin, synovial fluid, bone, cerebrospinal fluid, or lung), thus being a good alternative for the long-term treatment of orthopaedic implant infections, ventriculo-peritoneal shunts, and other infections related to foreign bodies in which gram-positive cocci are the main pathogens.

'Buffalo hump' adipose tissue shows specific disturbances in gene expression with respect to subcutaneous fat from HIV-1-infected/HAART-treated patients. Mitochondrial alterations cannot explain the differential behavior of 'buffalo hump' with respect to adipose depots prone to lipoatrophy. The absence of a local inflammatory status in 'buffalo hump' may explain in part the differential behavior of this adipose tissue.

We assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P ‫؍‬ 0.002) and TFV (P ‫؍‬ 0.0001). The combination of 10 M RTV and 40 M LPV significantly reduced RPTEC viability (P < 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs.Tenofovir disoproxil fumarate (TDF) is an oral prodrug of tenofovir (TFV), an acyclic nucleotide analogue reverse transcriptase inhibitor that is widely used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection (42). Controlled clinical studies in humans found TDF to be safe, with the incidence of TDF-associated renal impairment (elevated serum creatinine or hypophosphatemia) being 1 to 3% and with minimal differences from comparative non-TDF arms (22,23,29,30,34,50,62). However, several reports have reassessed the renal safety of TFV, and presently there is a progressively growing subset of TFV-treated patients presenting with acute renal failure, with Fanconi syndrome and/or nephrogenic diabetes insipidus, attributed to this drug (3, 10, 16, 18, 24-26, 32, 36-38, 40, 43, 46, 49, 51, 53, 55, 58-61, 66, 67). In the majority of cases the kidney damage was reversed upon discontinuation of TFV (71). Many of these case reports have suggested different mechanisms to explain the link between this drug and its attributed kidney toxicity, but at present this still remain largely elusive. Common features of most reports of TFV-related kidney toxicity were an advanced stage of HIV-1 infection and extensive pretreatment with antiretrovirals and other potentially nephrotoxic drugs before TFV was prescribed. The patients were receiving second, third, or even more advanced treatment regimens, which included in most cases lopinavir/ritonavir (LPV/RTV) and/or didanosine (ddI) in addition to TFV (3,10,16,18,[24][25][26]32,[36][37][38]40,43,46,...