To identify ultrastructural changes caused by the presence of HCV proteins, electron microscopic analyses were carried out. The study results revealed mitochondrial injury as a common defect among genome-length replicon, subgenomic replicon, and Core-on cells with enlarged mitochondria and focal loss of cristae ( Figure 1B ). Consistent with this observation, measurement of the cross sectional area of mitochondria directly from electron micrographs showed a significant increase in mitochondrial sizes ( Figure 2A ). The data indicates mitochondrial degeneration and the possible loss of mitochondria. Consequently, the number of mitochondria per cell was significantly reduced ( Figure 2B ). In addition to mitochondrial defects, accumulation of lipid droplets was common among all three HCV protein-expressing cell lines ( Figure 1B and Figure S2 ). Genome-length and subgenomic replicon cells also showed focally dilated rough endoplasmic reticulum (RER) and prominent presence of autophagocytic vacuoles ( Figures 1B and 3A ).