Figure 8.

Changes in mitochondrial morphology could be early adaptive responses after an APAP overdose: APAP induces centrilobular necrosis, where cells exposed to elevated concentrations of NAPQI form high levels of mitochondrial protein adducts leading to electron transport chain dysfunction and loss of membrane potential. This induces an adaptive response forming biconcave mitochondria, which under conditions of persistent membrane depolarization (in cells around the central vein) causes catastrophic mitochondrial functional failure with amplification of oxidant stress and induction of the mitochondrial permeability transition. The failure of this adaptive response, which presumably could have salvaged individual mitochondria then activates mitochondrial fission mediated by canonical proteins such as Drp1, which results in mitochondrial fragmentation. This could be an adaptive response in cells further away from the central vein exposed to lower levels of NAPQI, where mitochondrial fission allows mitophagy and mitochondrial biogenesis for cellular recovery at the cost of individual mitochondria. However, in cells closer to the portal vein exposed to much lower levels of NAPQI, where the decrease in mitochondrial membrane potential is transient, the adaptive biconcave mitochondrial morphology allows recovery of individual mitochondria and cell survival.