Role of Parkin in Acetaminophen-induced Mitophagy and Liver Injury
Jessica A. Williams, Hong-Min Ni, Wen-Xing Ding
University of Kansas Medical Center, Kansas City, KS
Autophagy is a catabolic process that degrades proteins and damaged organelles to promote cell survival. Mitophagy is a selective form of autophagy specific for degradation of mitochondria. Acetaminophen (APAP) overdose causes liver injury by inducing necrosis following mitochondrial damage, and we previously demonstrated that pharmacological induction of autophagy by rapamycin protected against APAP-induced liver injury in mice by degrading damaged mitochondria. However, the mechanism for this mitochondria removal by autophagy is unknown. Parkin, an E3 ligase, has been shown to be required for mitophagy induction in cultured mammalian cells following mitochondrial depolarization, but its role in vivo is not clear. The purpose of this study was to investigate the role of Parkininduced mitophagy in protection against APAP-induced liver injury using wild type (WT) and Parkin knockout (KO) mice. Parkin translocated to mitochondria in WT mouse livers after APAP treatment followed by mitophagy induction. We expected Parkin KO mice to have increased liver injury after APAP-overdose compared to WT mice due to their inability to induce mitophagy in the absence of Parkin. However, Parkin KO mice were actually protected against APAP-induced liver injury compared to WT mice as demonstrated by analysis of serum enzyme activity and liver tissue histology, and electron microscopy analysis surprisingly revealed that mitophagy still occurred in Parkin KO mice after APAP treatment. In addition, APAP increased mitochondrial protein ubiquitination and p62 mitochondrial translocation in both WT and Parkin KO mice, which provided further evidence of mitophagy induction in these mice. Even though it has been shown that Parkin is required for mitophagy induction in vitro, our data suggest that Parkin may not be essential for mitophagy induction in vivo. In addition, we found that Parkin KO mice had decreased activated c-Jun N-terminal kinase (JNK) and increased hepatocyte proliferation after APAP treatment in their livers compared to WT mice. In conclusion, these data suggest that Parkin is not essential for mitophagy induction in liver. Furthermore, Parkin may promote APAP-induced liver injury by enhancing APAPinduced JNK activation and impairing the liver repair process by inhibiting hepatocyte proliferation independent of its role in mitophagy.
The following people have nothing to disclose: Jessica A. Williams, Hong-Min Ni, Wen-Xing Ding