Figure 7: Proposed mechanism of TFV and ADV induced renal toxicity in the proximal tubule (PT) cells.

TFV and ADV is taken up from blood into PT cells via basolateral membrane OAT1/3 and is subsequently secreted from PT cells into urine through apical membrane efflux MRP4. Due to abnormal transport or other genetic factors, accumulated TFV concentrations inside PT cells will reduce mtDNA level by inhibiting SSBP1 and TWINKLE protein responsible for mtDNA replication. mtDNA is involved in many oxidative phosphorylation and damage of mtDNA induces disruption of ATP production. Among the genes regulated by TFV and ADV treatments, mitochondrial chaperone TRAP1 may play a central role in reprograming glucose metabolism by inhibiting its glucose oxidative phosphorylation and increasing glycolysis and glycogen synthesis. That is, down-regulation of PDHα and SDHB in TCA cycle and increasing protein levels of GLUT1, HK, PFK, PKM and GYS in glycolysis and glycogen synthesis. Elevation of bioenergetic genes ACLY and GLUL may help cells to generate energy from other sources like glutamine or lipid. Increased glycogen accumulation may be toxic for renal tubule cell function.