The Role of the Optic Atrophy 1 (OPA1) Protein in Drug-Induced Liver Injury

Hakjoo Lee, Hiromi Sesaki, Yisang Yoon

Research output: Contribution to journalArticlepeer-review


The liver is the metabolic hub, and is responsible for the myriad of processes including the nutrient homeostasis and detoxification. Mitochondria of liver are critical for these functions. The detoxification process in liver, when severe, often results in liver damage through causing oxidative stress. Mitochondria are the main source of ROS and are also vulnerable to oxidant damage. Therefore, mitochondrial dysfunction is one of the prominent causes for drug-induced liver injury. Mitochondrial fission and fusion, the main processes of mitochondrial dynamics, determine mitochondrial shape, and are important for functional maintenance of mitochondria. However, the role of mitochondrial dynamics in drug-induced liver injury is poorly understood. In the current study, we examined the role of the optic atrophy 1 (OPA1) protein in drug-induced liver injury. OPA1 is associated with mitochondrial inner membrane (IM) and mediates IM fusion. OPA1 also regulates cristate structure, and is required for proper electron transport and ATP production. To investigate the OPA1's role, we used liver-specific OPA1-knockout (OPA1-LKO) mice with acetaminophen (APAP) administration as a model for drug-induced liver injury. We generated OPA1-LKO mice by crossing OPA1 flox mice with mice carrying the Cre recombinase under the albumin promoter. Whereas whole body KO of OPA1 causes embryonic lethality, OPA1-LKO mice appeared healthy and showed normal growth and behavior. Although the OPA1 gene in the liver was disrupted, OPA1-LKO mice showed approximately 30% of OPA1 remaining in the liver, presumably due to less efficient albumin promoter-mediated Cre expression and from other cell types of the liver. Liver histology revealed that OPA1-KO livers have disorganized hepatic cords with enlarged hepatocytes. Despite a reduced OPA1 level, mitochondria in OPA1-KO liver show near intact cristae structure and respiration, suggesting that a low level of OPA1 would support mitochondrial function in liver. We then tested the effect of OPA1 LKO on liver function under APAP stress. In APAP overdose, excess APAP metabolite depletes GSH in hepatocytes, which causes mitochondrial oxidative stress, leading to mitochondrial permeability transition, mitochondrial dysfunction, ATP depletion, and ultimately necrotic cell death. Upon administration of excess APAP, we found that OPA1-LKO mice were more sensitive to APAP-induced liver injury compared with the control mice. Histological analyses showed significantly more expanded focal centrilobular necrosis with vacuolization, cell swelling, and nuclear disintegration in OPA1-KO livers. Alanine aminotransferase levels, as a clinical chemistry parameter, were higher in OPA1-LKO mice than in control mice with APAP overdose. Furthermore, phospho-JNK levels were higher in OPA1-KO livers, indicating increased initial oxidative stress. However, depletion of hepatic glutathione (GSH) contents and reduction of GSH/GSSG ratio upon APAP treatment were similar between the LKO and control liver. Together, our experimental results indicate that although liver is tolerant to a reduced level of OPA1, OPA1 depletion lowers the stress threshold and makes hepatocytes more sensitive to APAP-induced liver injury.

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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