Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Adenine/*analogs & derivatives ; Anti-HIV Agents/*adverse effects ; HSP90 Heat-Shock Proteins/*metabolism ; Mitochondria/*drug effects ; Mitochondria/*metabolism ; Organophosphonates/*adverse effects ; Succinate Dehydrogenase/*metabolism ; Tenofovir/*adverse effects; Adenine/adverse effects ; Animals ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Glucose/metabolism ; Glycolysis/drug effects ; HSP90 Heat-Shock Proteins/genetics ; Humans ; Kidney Diseases/etiology ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Mice ; Mitochondria/genetics ; Models, Biological ; Proteome ; Proteomics ; Succinate Dehydrogenase/genetics

Despite the therapeutic success of tenofovir (TFV) for treatment of HIV-1 infection, numerous cases of nephrotoxicity have been reported. Mitochondrial toxicity has been purported as the major target of TFV-associated renal tubulopathy but the underlying molecular mechanism remains unclear. In this report, we use metabolomics and proteomics with HK-2 cells and animal models to dissect the molecular pathways underlying nephropathy caused by TFV and its more toxic analog, adefovir (ADV). Proteomic analysis shows that mitochondrial chaperone TRAP1 and mtDNA replicating protein SSBP1 were significantly down-regulated in TFV and ADV treated HK-2 cells compared with controls. Transmission electron microscopy (TEM) revealed that TFV and ADV-treated HK-2 cells had accumulated glycogen, a phenotype that was also observed in mice treated with TFV and ADV. Analysis of the proteins in TCA cycle showed succinate dehydrogenase subunit B (SDHB) was nearly depleted in glucose oxidative phosphorylation pathway however certain enzymes in the glycolysis and glycogen synthesis pathway had elevated expression in TFV and ADV-treated HK-2 cells. These results suggest that TFV and ADV may cause mitochondrial dysfunction in renal tubular cells and reprogramming of glucose metabolism. The resulting glycogen accumulation may partially contribute to TFV and ADV induced renal dysfunction.

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0 (Anti-HIV Agents)
0 (HSP90 Heat-Shock Proteins)
0 (Organophosphonates)
0 (Proteome)
0 (SDHD protein, human)
0 (TRAP1 protein, human)
6GQP90I798 (adefovir)
99YXE507IL (Tenofovir)
EC 1.3.99.1 (Succinate Dehydrogenase)
IY9XDZ35W2 (Glucose)
JAC85A2161 (Adenine)

Date Created: 20170412 Date Completed: 20181127 Latest Revision: 20240325

20240325

PMC5387747

10.1038/srep46344

28397817